Thiazole derivatives

ABSTRACT

A compound of the formula (I): R 1 —NH—X—Y-Z (I) wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof useful as a vascular adhesion protein-1 (VAP-1) inhibitor, a pharmaceutical composition, a method for preventing or treating a VAP-1 associated disease, especially macular edema, which method includes administering an effective amount of the compound or a pharmaceutically acceptable salt thereof to a mammal, and the like.

TECHNICAL FIELD

The present invention relates to a compound or a pharmaceuticallyacceptable salt thereof useful as a vascular adhesion protein-1inhibitor, a pharmaceutical composition comprising the compound or saltthereof as an active ingredient, a method for preventing or treating avascular adhesion protein-1 associated disease, especially macularedema, use of the compound, salt thereof or composition, and the like.

BACKGROUND ART

Vascular adhesion protein-1 (hereinafter to be abbreviated as VAP-1) isan amine oxidase (semicarbazide sensitive amine oxidase, SSAO) which isabundant in human plasma, and shows remarkably increased expression invascular endothelium and vascular smooth muscle of the inflammatoryregion. While the physiological role of VAP-1 has not been clarifieduntil recently, VAP-1 gene was cloned in 1998, and VAP-1 has beenreported to be a membrane protein that regulates rolling and migrationof lymphocyte and NK cell as an adhesion molecule under regulation ofexpression by inflammatory cytokine. Although the amine to be asubstrate is unknown, it is considered to be methylamine generated inany part of living organisms. It is also known that hydrogen peroxideand aldehydes produced due to the amine oxidase activity in the moleculeare important factors of adhesion activity.

A recent report has documented that VAP-1 enzyme activity in plasmaincreases in diabetic patients, whether type I or type II, and theincrease is particularly remarkable in diabetic patients suffering fromretinopathy complications (Diabetologia, 42 (1999) 233–237, DiabeticMedicine, 16 (1999) 514–521).

In addition, it has been reported that VAP-1 is associated with thefollowing diseases:

-   (1) cirrhosis, essential stabilized hypertension, diabetes,    arthrosis (see JP-A-61-239891 and U.S. Pat. No. 4,888,283);-   (2) endothelium damage (in diabetes, atherosclerosis and    hypertension), a cardiovascular disorder associated with diabetes    and uraemia, pain associated with gout and arthritis, retinopathy    (in diabetes patients) (see WO 93/23023);-   (3) an (connective tissue) inflammatory disease or condition    (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis    and osteoarthritis or degenerative joint disease, Reiter's syndrome,    Sjögren's syndrome, Behçet's syndrome, relapsing polychondritis,    systemic lupus erythematosus, discoid lupus erythematosus, systemic    sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis,    polymyalgia rheumatica, vasculitis, temporal arteritis,    polyarteritis nodosa, Wegener's granulomatosis, mixed connective    tissue disease, and juvenile rheumatoid arthritis); a    gastrointestinal inflammatory disease or condition [Crohn's disease,    ulcerative colitis, irritable bowel syndrome (spastic colon),    fibrotic conditions of the liver, inflammation of the oral mucosa    (stomatitis), and recurrent aphtous stomatitis]; a central nervous    system inflammatory disease or condition (multiple sclerosis,    Alzheimer's disease, and ischaemia-reperfusion injury associated    with ischemic stroke); a pulmonary inflammatory disease or condition    (asthma, adult respiratory distress syndrome, chronic obstructive    pulmonary disease); a (chronic) skin inflammatory disease or    condition (psoriasis, allegic lesions, lichen planus, pityriasis    rosea, contact dermatitis, atopic dermatitis, pityriasis rubra    pilaris); a disease related to carbohydrate metabolism (diabetes and    complications from diabetes) including microvascular and    macrovascular disease (atherosclerosis, vascular retinopathies,    retinopathy, nephropathy, nephrotic syndrome and neuropathy    (polyneuropathy, mononeuropathies and autonomic neuropathy), foot    ulcers, joint problems, and increased risk of infection); a disease    related to aberrations in adipocyte differentiation or function or    smooth muscle cell function (atherosclerosis and obesity); a    vascular disease [atheromatous ateriosclerosis, nonatheromatous    ateriosclerosis, ischemic heart disease including myocardial    infarction and peripheral arterial occlusion, Raynaud's disease and    phenomenon, thromboangiitis obliterans (Buerger's disease)]; chronic    arthritis; inflammatory bowel diseases; skin dermatoses (see WO    02/02090, WO 02/02541 and U.S. patent application publication No.    2002/0173521 A1);-   (4) diabetes mellitus (see WO 02/38152); and-   (5) SSAO-mediated complication [diabetes (insulin dependent diabetes    mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM))    and vascular complication (heart attack, angina, strokes,    amputations, blindness and renal failure)] (see WO 02/38153), and    the like.

Under the present circumstances, a drug treatment or prophylaxis of theabove diseases has been demanded.

Macular edema is a common ocular abnormality resulting from a vastetiology and characterized by perturbation of the integrity of theblood-retinal barrier of the perifoveal capillaries and the optic nervehead. Macular edema is known to include diabetic and non-diabetic ones.Macular edema as a diabetic complication is a disease state that canoccur in any stage of diabetic retinopathy, emerges before the onset ofneovascularization and causes a serious visual disorder. Macular area isa highly evolved part in retina and plays a key role in controlling theeyesight. Once the macular area suffers from edema, how mild the changemay be, it causes a significant failure of eyesight, and when leftunattended, the edema causes irreversible changes of macular tissue, andit is considered to encourage progress of retinopathy.

At present, for macular edema, laser beam photocoagulation and vitreoussurgery have been tried as a symptomatic therapy. However, irradiationof laser on the macular area is not easy and unnecessary lasertreatments may produce side effects (e.g., possible encouragement ofedema by causing inflammation). The vitreous surgery is considered toprovide effect in 70 percent of macular edema, but physical andeconomical burden on patients is high, and the incidence of recurrenceis also high. These treatment methods are not usually employed in theinitial stage of macular edema, particularly so in the stages when thedecrease of vision is comparatively small. Accordingly, a drug treatmentcomparatively easily applicable from the early stages of the disease hasbeen also demanded under the present circumstances.

DISCLOSURE OF INVENTION

The present inventors have intensively worked on the problem of drugtreatment of a VAP-1 associated disease and found that a VAP-1 inhibitoris useful for the prophylaxis or treatment of the disease, particularlymacular edema, and completed the present invention. Thus, the presentinvention provides the following.

-   [1] A compound of the formula (I) [hereinafter sometimes referred to    as Compound (I)]:    R¹—NH—X—Y-Z  (I)    wherein-   R¹ is acyl;-   X is a bivalent residue derived from optionally substituted    thiazole;-   Y is a bond, lower alkylene, lower alkenylene or —CONH—; and-   Z is a group of the formula:

-   wherein R² is a group of the formula: -A-B-D-E-   wherein A is a bond, lower alkylene, —NH— or —SO₂—;    -   B is a bond, lower alkylene, —CO— or —O—;    -   D is a bond, lower alkylene, —NH— or —CH₂NH—; and    -   E is optionally protected amino, —N═CH₂,

-   -   wherein    -   Q is —S— or —NH—; and    -   R³ is hydrogen, lower alkyl, lower alkylthio or —NH—R⁴ wherein        R⁴ is hydrogen, —NH₂ or lower alkyl;        or a pharmaceutically acceptable salt thereof.

-   [2] The compound of [1], wherein Z is a group of the formula:

-   wherein R² is a group of the formula:

-   (wherein G is a bond, —NHCOCH₂— or lower alkylene and R⁴ is    hydrogen, —NH₂ or lower alkyl); —NH₂; —CH₂NH₂; —CH₂ONH₂; —CH₂ON═CH₂;

or a pharmaceutically acceptable salt thereof.

-   [3] The compound of [2], wherein R² is a group of the formula:

-   (wherein G is a bond, —NHCOCH₂— or lower alkylene and R⁴ is hydrogen    or lower alkyl); —CH₂NH₂; —CH₂ONH₂; —CH₂ON═CH₂;

or a pharmaceutically acceptable salt thereof.

-   [4] The compound of any of [1] to [3], wherein R¹ is alkylcarbonyl    and X is a bivalent residue derived from thiazole optionally    substituted by methylsulfonylbenzyl, or a pharmaceutically    acceptable salt thereof.-   [5] The compound of [1], wherein the compound is-   N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,-   N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide,-   N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide,-   N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,    or-   N-(4-{2-[4-(2-{[amino(imino)methyl]amino}ethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide,    or a pharmaceutically acceptable salt thereof.-   [6] The compound of [1] or a pharmaceutically acceptable salt    thereof for use as a medicament.-   [7] A pharmaceutical composition, which comprises, as an active    ingredient, the compound of [1] or a pharmaceutically acceptable    salt thereof.-   [8] A method for producing a compound of the formula (I):    R¹—NH—X—Y-Z  (I)    wherein-   R¹ is acyl;-   X is a bivalent residue derived from optionally substituted    thiazole;-   Y is a bond, lower alkylene, lower alkenylene or —CONH—; and-   Z is a group of the formula:

-   wherein R² is a group of the formula: -A-B-D-E-   wherein A is a bond, lower alkylene, —NH— or —SO₂—;    -   B is a bond, lower alkylene, —CO— or —O—;    -   D is a bond, lower alkylene, —NH— or —CH₂NH—; and    -   E is optionally protected amino, —N═CH₂,

-   -   wherein    -   Q is —S— or —NH—; and    -   R³ is hydrogen, lower alkyl, lower alkylthio or —NH—R⁴ wherein        R⁴ is hydrogen, —NH₂ or lower alkyl;

-   or a pharmaceutically acceptable salt thereof, which method    comprises at least one step selected from the group consisting    of (i) to (v):

-   (i) reacting Compound (1):

-   with Compound (2):

-   wherein L₁ is a leaving group and Z is as defined above, or a salt    thereof;-   (ii) reacting Compound (3): H₂N—X-Z-   wherein X and Z are as defined above, or a salt thereof with    Compound (4): R¹-L₂-   wherein R¹ is as defined above and L₂ is a leaving group;-   (iii) reacting Compound (6): R¹—NH—X—CHO-   wherein R¹ and X are as defined above, or a salt thereof with    Compound (7): L₃-CH₂-Z-   wherein L₃ is a leaving group and Z is as defined above, or a salt    thereof;-   (iv) reduction of Compound (10): R¹—NH—X— (lower alkenylene)-Z-   wherein R¹, X and Z are as defined above, or a salt thereof to    Compound (11): R¹—NH—X-(lower alkylene)-Z-   wherein R¹, X and Z are as defined above, or a salt thereof; and-   (v) reacting Compound (12): R¹—NH—X—COOH or a reactive derivative    thereof, wherein R¹ and X are as defined above, or a salt thereof    with Compound (13): L₄-NH-Z-   wherein L⁴ is a hydrogen atom or a protecting group and Z is as    defined above, or a salt thereof.-   [9] A use of the compound of [1] or a pharmaceutically acceptable    salt thereof for preparing a medicament as a VAP-1 inhibitor.-   [10] The use of [9], wherein the compound is-   N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,-   N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide,-   N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide,-   N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,    or-   N-(4-{2-[4-(2-{[amino(imino)methyl]amino}ethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide.-   [11] A use of the compound of [1] or a pharmaceutically acceptable    salt thereof for preparing a medicament for the prophylaxis or    treatment of a VAP-1 associated disease.-   [12] The use of [11], wherein said VAP-1 associated disease is    selected from the group consisting of cirrhosis, essential    stabilized hypertension, diabetes, arthrosis, endothelium damage (in    diabetes, atherosclerosis and hypertension), a cardiovascular    disorder associated with diabetes and uraemia, pain associated with    gout and arthritis, retinopathy (in diabetes patients), an    (connective tissue) inflammatory disease or condition (rheumatoid    arthritis, ankylosing spondylitis, psoriatic arthritis and    osteoarthritis or degenerative joint disease, Reiter's syndrome,    Sjögren's syndrome, Behçet's syndrome, relapsing polychondritis,    systemic lupus erythematosus, discoid lupus erythematosus, systemic    sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis,    polymyalgia rheumatica, vasculitis, temporal arteritis,    polyarteritis nodosa, Wegener's granulomatosis, mixed connective    tissue disease, and juvenile rheumatoid arthritis), a    gastrointestinal inflammatory disease or condition [Crohn's disease,    ulcerative colitis, irritable bowel syndrome (spastic colon),    fibrotic conditions of the liver, inflammation of the oral mucosa    (stomatitis), and recurrent aphtous stomatitis], a central nervous    system inflammatory disease or condition (multiple sclerosis,    Alzheimer's disease, and ischaemia-reperfusion injury associated    with ischemic stroke), a pulmonary inflammatory disease or condition    (asthma, adult respiratory distress syndrome, chronic obstructive    pulmonary disease), a (chronic) skin inflammatory disease or    condition (psoriasis, allegic lesions, lichen planus, pityriasis    rosea, contact dermatitis, atopic dermatitis, pityriasis rubra    pilaris), a disease related to carbohydrate metabolism (diabetes and    complications from diabetes) including microvascular and    macrovascular disease (atherosclerosis, vascular retinopathies,    retinopathy, nephropathy, nephrotic syndrome and neuropathy    (polyneuropathy, mononeuropathies and autonomic neuropathy), foot    ulcers, joint problems, and increased risk of infection), a disease    related to aberrations in adipocyte differentiation or function or    smooth muscle cell function (atherosclerosis and obesity), a    vascular disease [atheromatous ateriosclerosis, nonatheromatous    ateriosclerosis, ischemic heart disease including myocardial    infarction and peripheral arterial occlusion, Raynaud's disease and    phenomenon, thromboangiitis obliterans (Buerger's disease)], chronic    arthritis, inflammatory bowel diseases, skin dermatoses, diabetes    mellitus, SSAO-mediated complication [diabetes (insulin dependent    diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus    (NIDDM)) and vascular complication (heart attack, angina, strokes,    amputations, blindness and renal failure)] and macular edema    (diabetic and non-diabetic macular edema).-   [13] The use of [12], wherein said VAP-1 associated disease is    macular edema.-   [14] The use of [13], wherein said macular edema is diabetic macular    edema.-   [15] The use of [13], wherein said macular edema is non-diabetic    macular edema.-   [16] A VAP-1 inhibitor, which comprises the compound of [1] or a    pharmaceutically acceptable salt thereof.-   [17] A method for preventing or treating macular edema, which method    comprises administering to a subject in need thereof a VAP-1    inhibitor in an amount sufficient to treat said subject for macular    edema.-   [18] The method of [17], wherein the VAP-1 inhibitor is-   N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,-   N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide,-   N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide,-   N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,    or-   N-(4-{2-[4-(2-{[amino(imino)methyl]amino}ethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide,    or a pharmaceutically acceptable salt thereof.-   [19] A method for preventing or treating a VAP-1 associated disease,    which method comprises administering an effective amount of the    compound of [1] or a pharmaceutically acceptable salt thereof to a    mammal.-   [20] The method of [19], wherein said VAP-1 associated disease is    selected from the group consisting of cirrhosis, essential    stabilized hypertension, diabetes, arthrosis, endothelium damage (in    diabetes, atherosclerosis and hypertension), a cardiovascular    disorder associated with diabetes and uraemia, pain associated with    gout and arthritis, retinopathy (in diabetes patients), an    (connective tissue) inflammatory disease or condition (rheumatoid    arthritis, ankylosing spondylitis, psoriatic arthritis and    osteoarthritis or degenerative joint disease, Reiter's syndrome,    Sjögren's syndrome, Behçet's syndrome, relapsing polychondritis,    systemic lupus erythematosus, discoid lupus erythematosus, systemic    sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis,    polymyalgia rheumatica, vasculitis, temporal arteritis,    polyarteritis nodosa, Wegener's granulomatosis, mixed connective    tissue disease, and juvenile rheumatoid arthritis), a    gastrointestinal inflammatory disease or condition [Crohn's disease,    ulcerative colitis, irritable bowel syndrome (spastic colon),    fibrotic conditions of the liver, inflammation of the oral mucosa    (stomatitis), and recurrent aphtous stomatitis], a central nervous    system inflammatory disease or condition (multiple sclerosis,    Alzheimer's disease, and ischaemia-reperfusion injury associated    with ischemic stroke), a pulmonary inflammatory disease or condition    (asthma, adult respiratory distress syndrome, chronic obstructive    pulmonary disease), a (chronic) skin inflammatory disease or    condition (psoriasis, allegic lesions, lichen planus, pityriasis    rosea, contact dermatitis, atopic dermatitis, pityriasis rubra    pilaris), a disease related to carbohydrate metabolism (diabetes and    complications from diabetes) including microvascular and    macrovascular disease (atherosclerosis, vascular retinopathies,    retinopathy, nephropathy, nephrotic syndrome and neuropathy    (polyneuropathy, mononeuropathies and autonomic neuropathy), foot    ulcers, joint problems, and increased risk of infection), a disease    related to aberrations in adipocyte differentiation or function or    smooth muscle cell function (atherosclerosis and obesity), a    vascular disease [atheromatous ateriosclerosis, nonatheromatous    ateriosclerosis, ischemic heart disease including myocardial    infarction and peripheral arterial occlusion, Raynaud's disease and    phenomenon, thromboangiitis obliterans (Buerger's disease)], chronic    arthritis, inflammatory bowel diseases, skin dermatoses, diabetes    mellitus, SSAO-mediated complication [diabetes (insulin dependent    diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus    (NIDDM)) and vascular complication (heart attack, angina, strokes,    amputations, blindness and renal failure)] and macular edema    (diabetic and non-diabetic macular edema).-   [21] The method of [20], wherein said VAP-1 associated disease is    macular edema.-   [22] The method of [21], wherein said macular edema is diabetic    macular edema.-   [23] The method of [21], wherein said macular edema is non-diabetic    macular edema.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is predicated on the discovery that an inhibitorof vascular adhesion protein-1 (VAP-1; also referred to as semicarbazidesensitive amine oxidase (SSAO) or copper-containing amine oxidase) iseffective in treating or ameliorating a VAP-1 associated disease,especially macular edema, and the like. Accordingly, the presentinvention provides Compound (I) or a pharmaceutically acceptable saltthereof useful as a VAP-1 inhibitor, a pharmaceutical composition, amethod for preventing or treating a VAP-1 associated disease, and thelike.

In the above and subsequent descriptions of the present specification,suitable examples and illustration of the various definitions to beincluded within the scope of the invention are explained in detail asfollows.

Suitable “halogen” includes fluorine, chlorine, bromine and iodine.

The term “lower” is used to intend a group having 1 to 6, preferably 1to 4, carbon atom(s), unless otherwise provided.

Suitable “lower alkyl” includes straight or branched alkyl having 1 to 6carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl and hexyl, in whichmore preferred one is C₁–C₄ alkyl.

Suitable “lower alkylthio” includes lower alkylthio containing the abovelower alkyl, such as methylthio, ethylthio, propylthio, isopropylthio,butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio,tert-pentylthio and hexylthio.

Suitable “lower alkylene” includes straight or branched alkylene having1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene,tetramethylene, propylene, ethylidene and propylidene, in which morepreferred one is C₁–C₄ alkylene.

Suitable “lower alkenylene” includes straight or branched alkenylenehaving 2 to 6 carbon atom(s), such as —CH═CH—, —CH₂—CH═CH—,—CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—, —CH═CH—CH═CH—, —CH═CH—CH₂—CH₂—CH₂—,—CH═CH—CH═CH—CH₂—CH₂— and —CH═CH—CH═CH—CH═CH—, in which more preferredone is C₂–C₄ alkenylene.

The above lower alkenylene may be in E or Z form, respectively. Thus,those skilled in the art will recognize that the lower alkenyleneincludes all E, Z-structures when it has 2 or more double bonds.

Suitable “aryl” includes C₆–C₁₀ aryl such as phenyl and naphthyl, inwhich more preferred one is phenyl. The “aryl” may be substituted by 1to 3 substituent(s) and the substitution sites are not particularlylimited.

Suitable “aralkyl” includes aralkyl wherein the aryl moiety has 6 to 10carbon atoms [i.e. the aryl moiety is C₆–C₁₀ aryl of the above “aryl”]and the alkyl moiety has 1 to 6 carbon atom(s) [i.e. the alkyl moiety isC₁–C₆ alkyl of the above “lower alkyl”], such as benzyl, phenethyl,1-naphthylmethyl, 2-naphthylmethyl, 3-phenylpropyl, 4-phenylbutyl and5-phenylpentyl.

The “optionally protected amino” means that an amino group may beprotected with a suitable protecting group according to a method knownper se, such as the methods described in Protective Groups in OrganicSynthesis, published by John Wiley and Sons (1980), and the like. Thesuitable “protecting group” includes tert-butoxycarbonyl (i.e., Boc), anacyl group as mentioned below, substituted or unsubstitutedaryl(lower)alkylidene [e.g., benzylidene, hydroxybenzylidene, etc.],aryl(lower)alkyl such as mono-, di- or triphenyl-(lower)alkyl [e.g.,benzyl, phenethyl, benzhydryl, trityl, etc.] and the like.

Suitable “optionally protected amino” includes amino andtert-butoxycarbonylamino (i.e. —NHBoc).

Suitable “heterocycle” includes “aromatic heterocycle” and “non-aromaticheterocycle”.

Suitable “aromatic heterocycle” includes 5 to 10-membered aromaticheterocycle containing 1 to 3 heteroatom(s) selected from nitrogen,oxygen and sulfur atoms besides carbon atom(s), and includes, forexample, thiophene, furan, pyrrole, imidazole, pyrazole, thiazole,isothiazole, oxazole, isoxazole, pyridine, pyridazine, pyrimidine,pyrazine and the like.

Suitable “non-aromatic heterocycle” includes 5 to 10-memberednon-aromatic heterocycle containing 1 to 3 heteroatom(s) selected fromnitrogen, oxygen and sulfur atoms besides carbon atom(s), and includes,for example, pyrrolidine, imidazoline, pyrazolidine, pyrazoline,piperidine, piperazine, morpholine, thiomorpholine, dioxolan,oxazolidine, thiazolidine, triazolidine and the like.

Suitable “acyl” includes acyl having 1 to 20 carbon atom(s), such asformyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl andaralkyloxycarbonyl.

Suitable “alkylcarbonyl” includes alkylcarbonyl wherein the alkyl moietyhas 1 to 6 carbon atom(s) [i.e. the alkyl moiety is C₁–C₆ alkyl of theabove “lower alkyl”], such as acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl, pivaloyl, hexanoyl and heptanoyl, in which morepreferred one is C₁–C₄ alkyl-carbonyl.

Suitable “arylcarbonyl” includes arylcarbonyl wherein the aryl moietyhas 6 to 10 carbon atom(s) [i.e. the aryl moiety is C₆–C₁₀ aryl of theabove “aryl”], such as benzoyl and naphthoyl.

Suitable “alkoxycarbonyl” includes alkoxycarbonyl wherein the alkoxymoiety has 1 to 6 carbon atom(s), such as methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,pentyloxycarbonyl, tert-pentyloxycarbonyl and hexyloxycarbonyl, in whichmore preferred one is alkoxycarbonyl wherein the alkoxy moiety has 1 to4 carbon atom(s).

Suitable “aralkyloxycarbonyl” includes aralkyloxycarbonyl wherein thearyl moiety has 6 to 10 carbon atom(s) [i.e. the aryl moiety is C₆–C₁₀aryl of the above “aryl”] and the alkyl moiety has 1 to 6 carbon atom(s)[i.e. the alkyl moiety is C₁–C₆ alkyl of the above “lower alkyl”], suchas benzyloxycarbonyl, phenethyloxycarbonyl, 1-naphthylmethyloxycarbonyl,2-naphthylmethyloxycarbonyl, 3-phenylpropyloxycarbonyl,4-phenylbutyloxycarbonyl and 5-phenylpentyloxycarbonyl.

Suitable “bivalent residue derived from thiazole” of the “bivalentresidue derived from optionally substituted thiazole” includes

The “thiazole” may have 1 to 3 substituent(s) and the substitution sitesare not particularly limited.

Suitable “substituent” of the above “optionally substituted thiazole”includes, for example,

(1) halogen which is as defined above;

(2) alkoxycarbonyl which is as defined above, such as ethoxycarbonyl;

(3) optionally substituted aryl, which aryl is as defined above and thesubstitution sites are not particularly limited, such as phenyl and4-(methylsulfonyl)phenyl;

(4) a group of the formula: —CONR^(a)R^(b) wherein R^(a) is hydrogen,lower alkyl, aryl or aralkyl and R^(b) is hydrogen, lower alkyl, aryl oraralkyl, wherein the lower alkyl, aryl and aralkyl are as defined above,such as N-methylaminocarbonyl, N-phenylaminocarbonyl,N,N-dimethylaminocarbonyl and N-benzylaminocarbonyl;

(5) a group of the formula: —CONH—(CH₂)_(k)-aryl

wherein k is an integer of 0 to 6; the aryl is as defined above, whichmay have 1 to 5 substituent(s) selected from the group consisting of—NO₂, —SO₂-(lower alkyl) wherein the lower alkyl is as defined above,—CF₃ and —O-aryl wherein the aryl is as defined above, and thesubstitution sites are not particularly limited;

(6) a group of the formula: —CONH—(CH₂)_(m)-heterocycle

wherein m is an integer of 0 to 6; the heterocycle is as defined above,such as pyridine;

(7) a group of the formula: —CO-heterocycle

wherein the heterocycle is as defined above, such as pyrrolidine,piperidine, piperazine, thiomorpholine, which may have 1 to 5substituent(s) selected from the group consisting of —CO-(lower alkyl)wherein the lower alkyl is as defined above, —CO—O-(lower alkyl) whereinthe lower alkyl is as defined above, —SO₂-(lower alkyl) wherein thelower alkyl is as defined above, oxo (i.e. ═O) and a group of theformula: —CONR^(c)R^(d) wherein R^(c) is hydrogen, lower alkyl, aryl oraralkyl and R^(d) is hydrogen, lower alkyl, aryl or aralkyl wherein thelower alkyl, aryl and aralkyl are as defined above, and the substitutionsites are not particularly limited;

(8) a group of the formula: —(CH₂)_(n)-aryl

wherein n is an integer of 1 to 6; the aryl is as defined above, whichmay have 1 to 5 substituent(s) selected from the group consisting of—S-(lower alkyl) wherein the lower alkyl is as defined above,—SO₂-(lower alkyl) wherein the lower alkyl is as defined above,—CO₂-(lower alkyl) wherein the lower alkyl is as defined above,—NHCO—O-(lower alkyl) wherein the lower alkyl is as defined above and agroup of the formula: —CONR^(e)R^(f) wherein R^(e) is hydrogen, loweralkyl, aryl or aralkyl and R^(f) is hydrogen, lower alkyl, aryl oraralkyl wherein the lower alkyl, aryl and aralkyl are as defined above,and the substitution sites are not particularly limited;

(9) a group of the formula: —(CH₂)_(o)-heterocycle

wherein o is an integer of 0 to 6; the heterocycle is as defined above,such as pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine,which may have 1 to 5 substituent(s) selected from the group consistingof oxo (i.e. ═O); —CO-(lower alkyl) wherein the lower alkyl is asdefined above; —CO—O-(lower alkyl) wherein the lower alkyl is as definedabove; —SO₂-(lower alkyl) wherein the lower alkyl is as defined above;—CO-(heterocycle) wherein the heterocycle is as defined above such aspyrrolidine, piperazine and morpholine, which may have 1 to 5substituent(s) selected from the group consisting of lower alkyl andhalogen, wherein the lower alkyl and halogen are as defined above, andthe substitution sites are not particularly limited; and a group of theformula: —CONR^(g)R^(h) wherein R^(g) is hydrogen, lower alkyl, aryl oraralkyl and R^(h) is hydrogen, lower alkyl, aryl or aralkyl wherein thelower alkyl, aryl and aralkyl are as defined above, and the substitutionsites are not particularly limited;

(10) a group of the formula: —(CH₂)_(p)—NR^(i)R^(j)

wherein p is an integer of 0 to 6; R^(i) is hydrogen, acyl, lower alkyl,aryl or aralkyl and R^(j) is hydrogen, acyl, lower alkyl, aryl oraralkyl wherein the acyl, lower alkyl, aryl and aralkyl are as-definedabove, and the lower alkyl may have 1 to 5 substituent(s) selected fromthe group consisting of a group of the formula: —CONR^(k)R^(l) whereinR^(k) is hydrogen, lower alkyl, aryl or aralkyl and R^(l) is hydrogen,lower alkyl, aryl or aralkyl wherein the lower alkyl, aryl and aralkylare as defined above, and the substitution sites are not particularlylimited;

(11) a group of the formula: —CON(H or lower alkyl)-(CHR^(m))_(q)-T

wherein q is an integer of 0 to 6; the lower alkyl is as defined above;R^(m) is hydrogen, aralkyl which is as defined above, or alkyl which isas defined above, which may be substituted by 1 to 3 substituent(s)selected from the group consisting of —OH and —CONH₂ and thesubstitution sites are not particularly limited; and T is hydrogen; agroup of the formula: —CONR^(n)R^(o) wherein R^(n) is hydrogen, loweralkyl, aryl or aralkyl and R^(o) is hydrogen, lower alkyl, aryl oraralkyl wherein the lower alkyl, aryl and aralkyl are as defined above;—NH—CO—R^(p) wherein R^(p) is lower alkyl which is as defined above oraralkyl which is as defined above; —NH—SO₂-(lower alkyl) wherein thelower alkyl is as defined above; —SO₂-(lower alkyl) wherein the loweralkyl is as defined above; -heterocycle wherein the heterocycle is asdefined above, such as pyridine, pyrrolidine and morpholine, which mayhave 1 to 3 substituent(s) such as oxo (i.e. ═O), and the substitutionsites are not particularly limited; or —CO-(heterocycle) wherein theheterocycle is as defined above, such as piperidine and morpholine; and

(12) a group of the formula: —(CH₂)_(r)—CO—NR^(t)R^(u)

wherein r is an integer of 1 to 6; R^(t) is hydrogen, lower alkyl, arylor aralkyl and R^(u) is hydrogen, lower alkyl, aryl or aralkyl whereinthe lower alkyl, aryl and aralkyl are as defined above.

The substitution site on the aryl or heterocycle is any suitableposition thereof, but not particularly limited.

Preferable “substituent” of the above “optionally substituted thiazole”is methylsulfonylbenzyl.

The substitution sites of R² on the phenyl in Compound (I) is notparticularly limited.

When Z is a group of the formula:

the substitution sites on the group are not particularly limited.

is particularly preferable.

Any nitrogen atom in the amino (i.e. —NH₂), imino (i.e. ═NH or —NH—) orthe like contained in Compound (I) may be protected according to themethods, which are known to those skilled in the art, such as themethods described in Protective Groups in Organic Synthesis, publishedby John Wiley and Sons (1980), and the like.

When Compound (I) has an asymmetric carbon atom in the structure, thoseskilled in the art will recognize that Compound (I) includes allstereoisomers.

The “vascular adhesion protein-1 (VAP-1) associated disease” comprise adisease selected from the group consisting of cirrhosis, essentialstabilized hypertension, diabetes, arthrosis; endothelium damage (indiabetes, atherosclerosis and hypertension), a cardiovascular disorderassociated with diabetes and uraemia, pain associated with gout andarthritis, retinopathy (in diabetes patients); an (connective tissue)inflammatory disease or condition (rheumatoid arthritis, ankylosingspondylitis, psoriatic arthritis and osteoarthritis or degenerativejoint disease, Reiter's syndrome, Sjögren's syndrome, Behçet's syndrome,relapsing polychondritis, systemic lupus erythematosus, discoid lupuserythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis,dermatomyositis, polymyalgia rheumatica, vasculitis, temporal arteritis,polyarteritis nodosa, Wegener's granulomatosis, mixed connective tissuedisease, and juvenile rheumatoid arthritis); a gastrointestinalinflammatory disease or condition [Crohn's disease, ulcerative colitis,irritable bowel syndrome (spastic colon), fibrotic conditions of theliver, inflammation of the oral mucosa (stomatitis), and recurrentaphtous stomatitis]; a central nervous system inflammatory disease orcondition (multiple sclerosis, Alzheimer's disease, andischaemia-reperfusion injury associated with ischemic stroke); apulmonary inflammatory disease or condition (asthma, adult respiratorydistress syndrome, chronic obstructive pulmonary disease); a (chronic)skin inflammatory disease or condition (psoriasis, allegic lesions,lichen planus, pityriasis rosea, contact dermatitis, atopic dermatitis,pityriasis rubra pilaris); a disease related to carbohydrate metabolism(diabetes and complications from diabetes) including microvascular andmacrovascular disease (atherosclerosis, vascular retinopathies,retinopathy, nephropathy, nephrotic syndrome and neuropathy(polyneuropathy, mononeuropathies and autonomic neuropathy), footulcers, joint problems, and increased risk of infection); a diseaserelated to aberrations in adipocyte differentiation or function orsmooth muscle cell function (atherosclerosis and obesity); a vasculardisease [atheromatous ateriosclerosis, nonatheromatous ateriosclerosis,ischemic heart disease including myocardial infarction and peripheralarterial occlusion, Raynaud's disease and phenomenon, thromboangiitisobliterans (Buerger's disease)]; chronic arthritis; inflammatory boweldiseases; skin dermatoses; diabetes mellitus; SSAO-mediated complication[diabetes (insulin dependent diabetes-mellitus (IDDM) and non-insulindependent diabetes mellitus (NIDDM)) and vascular complication (heartattack, angina, strokes, amputations, blindness and renal failure)];macular edema (e.g., diabetic and non-diabetic macular edema), and thelike.

The “preventing or treating a vascular adhesion protein-1 (VAP-1)associated disease” and “prophylaxis or treatment of a vascular adhesionprotein-1 (VAP-1) associated disease”, particularly “preventing ortreating macular edema” and “prophylaxis or treatment of macular edema”are intended to include administration of a compound having VAP-1inhibitory activity (i.e. VAP-1 inhibitor) to a subject for therapeuticpurposes, which may include prophylaxis, amelioration, prevention andcure of the above described VAP-1 associated disease, particularlymacular edema. As used herein, by the “subject” is meant a target of theadministration of VAP-1 inhibitor in the present invention, which isspecifically various animals such as mammal, e.g., human, mouse, rat,swine, dog, cat, horse, bovine and the like, especially human.

The method comprises administration of VAP-1 inhibitor in an amountsufficient to treat the VAP-1 associated disease, especially macularedema. Any VAP-1 inhibitor can be used in the method of the presentinvention as long as it is safe and efficacious. Herein, “VAP-1inhibitor” will be used to refer to such compounds, which includeCompound (I), and is intended to encompass all compounds that inhibitenzyme activity of VAP-1 at any and all points in the action mechanismthereof.

For example, the compounds of the present invention and derivativesthereof, or compounds reported to have inhibited VAP-1 enzyme (SSAO) mayinclude fluoroallylamine derivatives, semicarbazide derivatives,hydrazide derivatives, hydrazino derivatives, 1,3,4-oxadiazinederivatives, 2,6-diethoxybenzylamine, 2,6-di(n-propoxy)benzylamine,2,6-diisopropoxybenzylamine, 2,6-di(n-butoxy)benzylamine,2,6-bis(methoxymethoxy)benzylamine, 2,6-bis(methoxymethyl)benzylamine,2,6-diethylbenzylamine, 2,6-di-n-propylbenzylamine,2,6-bis(2-hydroxyethoxy)benzylamine, and the like.

The above compounds can be exemplified as follows.

-   1) fluoroallylamine derivatives, semicarbazide derivatives and    hydrazide derivatives described in WO 93/23023,-   2) hydrazino derivatives described in WO 02/02090,-   3) 1,3,4-oxadiazine derivatives described in WO 02/02541,-   4) 4-alkyl-5-alkoxycarbonyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine    derivatives described in WO 02/38153,-   5) 2,6-diethoxybenzylamine, 2,6-di(n-propoxy)benzylamine,    2,6-diisopropoxybenzylamine, 2,6-di(n-butoxy)benzylamine,    2,6-bis(methoxymethoxy)benzylamine,    2,6-bis(methoxymethyl)benzylamine, 2,6-diethylbenzylamine,    2,6-di-n-propylbenzylamine and 2,6-bis(2-hydroxyethoxy)benzylamine    described in U.S. Pat. No. 4,888,283.

The compounds exemplified in the present invention as a VAP-1 inhibitorand in WO 93/23023 as an SSAO inhibitor, such as those described inLyles et al. (Biochem. Pharmacol. 36:2847, 1987) and in U.S. Pat. No.4,650,907, U.S. Pat. No. 4,916,151, U.S. Pat. No. 4,943,593, U.S. Pat.No. 4,965,288, U.S. Pat. No. 5,021,456, U.S. Pat. No. 5,059,714, U.S.Pat. No. 4,699,928, European patent application 295604, European patentapplication 224924 and European patent application 168013, are alsoencompassed in the VAP-1 inhibitor.

Of the above-mentioned compounds, preferred are Compound (I), morepreferably,

-   N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide    (hereinafter Compound A; see Production Example 1),-   N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide    (see Production Example 48),-   N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide    (see Production Example 50),-   N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide    (see Production Example 58), and-   N-(4-{2-[4-(2-{[amino(imino)methyl]amino}ethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide    (see Production Example 110),-   particularly    N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide    and derivatives thereof.

The term “derivative” is intended to include all compounds derived fromthe original compound.

In the present invention, the VAP-1 inhibitor can be administered as aprodrug to a subject. The term “prodrug” is intended to include allcompounds that convert to the VAP-1 inhibitor in the body ofadministration subject. The prodrug can be any pharmaceuticallyacceptable prodrug of VAP-1 inhibitor. Moreover, the VAP-1 inhibitor canbe administered to an administration subject as a pharmaceuticallyacceptable salt.

The pharmaceutically acceptable salt of VAP-1 inhibitor of the presentinvention is nontoxic and a pharmaceutically acceptable conventionalsalt, which is exemplified by salts with inorganic or organic base suchas alkali metal salt (e.g., sodium salt, potassium salt and the like),alkaline earth metal salt (e.g., calcium salt, magnesium salt and thelike), ammonium salt, and amine salt (e.g., triethylamine salt,N-benzyl-N-methylamine salt and the like).

The VAP-1 inhibitor can be also formulated as a pharmaceuticallyacceptable acid addition salt. Examples of the pharmaceuticallyacceptable acid addition salts for use in the pharmaceutical compositioninclude those derived from mineral acids, such as hydrochloric,hydrobromic, hydriodic, phosphoric, metaphosphoric, nitric and sulfuricacids, and organic acids, such as tartaric, acetic, citric, malic,lactic, fumaric, benzoic, glycolic, gluconic, succinic and arylsulfonicacids, for example, p-toluenesulfonic acid.

As a pharmaceutically acceptable salt of VAP-1 inhibitor represented bythe formula (I), a pharmaceutically acceptable acid addition salt suchas (mono-, di- or tri-) hydrochloride and hydriodide, particuralyhydrochloride, is preferable.

The above-mentioned VAP-1 inhibitor may be commercially available or canbe produced based on a known reference.

Also, Compound (I), particularly Compound A:N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,can be synthesized according to the Production Method given below.

Those compounds or derivatives thereof that are not commerciallyavailable can be prepared using organic synthetic methods known in theart.

The VAP-1 inhibitor or a pharmaceutically acceptable salt thereof can beadministered in accordance with the present inventive method by anysuitable route. Suitable routes of administration include systemic, suchas orally or by injection, topical, periocular (e.g., subTenon's),subconjunctival, intraocular, subretinal, suprachoroidal and retrobulbaradministrations. The manner in which the VAP-1 inhibitor is administeredis dependent, in part, upon whether the treatment of a VAP-1 associateddisease is prophylactic or therapeutic.

The VAP-1 inhibitor is preferably administered as soon as possible afterit has been determined that a subject such as mammal, specifically ahuman, is at risk for a VAP-1 associated disease (prophylactictreatments) or has begun to develop a VAP-1 associated disease(therapeutic treatments). Treatment will depend, in part, upon theparticular VAP-1 inhibitor to be used, the amount of the VAP-1 inhibitorto be administered, the route of administration, and the cause andextent, if any, of a VAP-1 associated disease realized.

One skilled in the art will appreciate that suitable methods ofadministering a VAP-1 inhibitor, which is useful in the presentinventive method, are available. Although more than one route can beused to administer a particular VAP-1 inhibitor, a particular route canprovide a more immediate and more effective reaction than another route.Accordingly, the described routes of administration are merely exemplaryand are in no way limiting.

The dose of the VAP-1 inhibitor administered to the administrationsubject such as animal including human, particularly a human, inaccordance with the present invention should be sufficient to effect thedesired response in the subject over a reasonable time frame. Oneskilled in the art will recognize that dosage will depend upon a varietyof factors, including the strength of the particular VAP-1 inhibitor tobe employed, the age, species, conditions or disease states, and bodyweight of the subject, as well as the degree of a VAP-1 associateddisease. The size of the dose also will be determined by the route,timing and frequency of administration as well as the existence, nature,and extent of any adverse side effects that might accompany theadministration of a particular VAP-1 inhibitor and the desiredphysiological effect. It will be appreciated by one of ordinary skill inthe art that various conditions or disease states may require prolongedtreatment involving multiple administrations.

Suitable doses and dosage regimens can be determined by conventionalrange-finding techniques known to those of ordinary skill in the art.Generally, treatment is initiated with smaller dosages, which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached.

Generally, the VAP-1 inhibitor can be administered in the dose of fromabout 1 μg/kg/day to about 300 mg/kg/day, preferably from about 0.1mg/kg/day to about 10 mg/kg/day, which is given in a single dose or 2 to4 doses a day or in a sustained manner.

Pharmaceutical compositions for use in the present inventive methodpreferably comprise a “pharmaceutically acceptable carrier” and anamount of a VAP-1 inhibitor sufficient to treat a VAP-1 associateddisease, especially macular edema, prophylactically or therapeuticallyas an active ingredient. The carrier can be any of those conventionallyused and is limited only by chemico-physical considerations, such assolubility and lack of reactivity with the compound, and by the route ofadministration.

The VAP-1 inhibitor can be administered in various manners to achievethe desired VAP-1 inhibitory effect. The VAP-1 inhibitors can beadministered alone or in combination with pharmaceutically acceptablecarriers or diluents, the properties and nature of which are determinedby the solubility and chemical properties of the inhibitor selected, thechosen administration route, and standard pharmaceutical practice. TheVAP-1 inhibitor may be administered orally in solid dosage forms, e.g.,capsules, tablets, powders, or in liquid forms, e.g., solutions orsuspensions. The inhibitor may also be injected parenterally in the formof sterile solutions or suspensions. Solid oral forms may containconventional excipients, for instance, lactose, sucrose, magnesiumstearate, resins, and like materials. Liquid oral forms may containvarious flavoring, coloring, preserving, stabilizing, solubilizing, orsuspending agents. Parenteral preparations are sterile aqueous ornon-aqueous solutions or suspensions which may contain certain variouspreserving, stabilizing, buffering, solubilizing, or suspending agents.If desired, additives, such as saline or glucose, may be added to makethe solutions isotonic.

The present inventive method also can involve the co-administration ofother pharmaceutically active compounds. By “co-administration” is meantadministration before, concurrently with, e.g., in combination with theVAP-1 inhibitor in the same formulation or in separate formulations, orafter administration of a VAP-1 inhibitor as described above. Forexample, corticosteroids, prednisone, methylprednisolone, dexamethasone,or triamcinolone acetinide, or noncorticosteroid anti-inflammatorycompounds, such as ibuprofen or flubiprofen, can be co-administered.Similarly, vitamins and minerals, e.g., zinc, anti-oxidants, e.g.,carotenoids (such as a xanthophyll carotenoid like zeaxanthin orlutein), and micronutrients can be co-administered.

In addition, the VAP-1 inhibitor according to the present invention isuseful for preparing a medicament such as a therapeutic or prophylacticagent for the VAP-1 associated diseases.

Production Method of Compound (I)

Compound (I) is prepared in accordance with, but is not limited to, thefollowing procedures. Those skilled in the art will recognize that theprocedures can be modified according to the conventional methods knownper se.

Procedure A: Synthesis of Compound (I) wherein Y is a bond

wherein

-   L₁ is a leaving group such as halogen (e.g., chlorine, bromine,    iodine);-   Z is as defined above;-   X is as defined above, in this case,

-   R¹ is acyl; and-   L₂ is a leaving group such as —OH, halogen (e.g., chlorine, bromine,    iodine), —O-acyl wherein the acyl is as defined above (e.g.,    —O-acetyl and the like).    Formation of Thiazole Moiety X

Compound (1) is reacted with Compound (2) or its salt to give Compound(3).

Suitable salt of Compound (2) may be the same as those exemplified forCompound (I).

Compounds (1) and (2) or its salt may be commercially available or canbe prepared in accordance with the methods known per se (see ProductionExample 11).

The reaction is usually carried out in a conventional solvent such asethanol, acetone, dichloromethane, acetic acid, and other organicsolvent which does not adversely affect the reaction, or a mixturethereof.

The reaction temperature is not critical, and the reaction can becarried out under cooling to heating.

Compound (3) thus obtained can be isolated or purified by knownseparation or purification means, such as concentration, concentrationin vacuo, solvent extraction, crystallization, recrystallization, phasetransfer, chromatography and the like, and can be converted to a saltsame as those exemplified for Compound (I).

Acylation

Compound (3) or its salt is reacted with Compound (4) to give Compound(5). Since R¹ is an acyl group, this reaction is an acylation.

The conventional acylation method may be employed in the presentinvention.

Compound (4) may be commercially available or can be prepared inaccordance with the methods known per se.

The reaction is usually carried out in a conventional solvent such asdichloromethane, chloroform, methanol, and other organic solvent whichdoes not adversely affect the reaction, or a mixture thereof.

The reaction is also preferably carried out in the presence of aconventional base such as 4-dimethylaminopyridine, pyridine etc. Aliquid base can be also used as the solvent.

The reaction temperature is not critical, and the reaction can becarried out under cooling to heating.

Compound (5) thus obtained can be isolated or purified by knownseparation or purification means, such as concentration, concentrationin vacuo, solvent extraction, crystallization, recrystallization, phasetransfer, chromatography and the like, and can be converted to a saltsame as those exemplified for Compound (I).

The acylation may be applied to Compound (1) in advance.

The nitrogen atom in Compound (1), (2), (3) or (5) may be protected ordeprotected, as necessary, in accordance with methods known-per se suchas the methods described in Protective Groups in Organic Synthesis,published by John Wiley and Sons (1980), and the like.

Procedure B: Synthesis of Compound (I) wherein Y is lower alkylene suchas ethylene (i.e. —CH₂—CH₂—) or lower alkenylene such as vinylene (i.e.—CH═CH—), for example,

wherein

-   L₃ is a leaving group such as halogen (e.g., chlorine, bromine,    iodine); and-   R¹, X and Z are as defined above.    Formation of Olefin Compound

Compound (6) or its salt is reacted with Compound (7) or its salt togive an olefin compound (8).

Suitable salts of Compounds (6) and (7) may be the same as thoseexemplified for Compound (I).

Compounds (6) and (7) or salts thereof may be commercially available orcan be prepared in accordance with the methods known per se (seeProduction Example 1 and 3).

The reaction is usually carried out in a conventional solvent such asN,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran,dichloromethane, and other organic solvent which does not adverselyaffect the reaction, or a mixture thereof.

The reaction is also usually carried out in the presence oftriphenylphosphine and a conventional base such as potassiumtert-butoxide, sodium hydride, sodium hydroxide and the like.

The reaction temperature is not critical, and the reaction can becarried out under cooling to heating.

Compound (8) thus obtained can be isolated or purified by knownseparation or purification means, such as concentration, concentrationin vacuo, solvent extraction, crystallization, recrystallization, phasetransfer, chromatography and the like, and can be converted to a saltsame as those exemplified for Compound (I).

Reduction

Compound (8) or its salt is reduced in accordance with a conventionalmethod to give Compound (9).

The conventional reduction includes hydrogenation, catalytichydrogenation, etc.

Among others, catalytic hydrogenation is preferable.

The catalytic hydrogenation is carried out in the presence of a catalystsuch as palladium carbon, preferably 10% palladium carbon.

The catalytic hydrogenation is usually carried out in a conventionalsolvent such as tetrahydrofuran, ethanol, ethyl acetate, and othersolvent which does not adversely affect the reaction, or a mixturethereof.

The catalytic hydrogenation is also preferably carried out in thepresence of a conventional acid such as acetic acid, hydrochloric acidand the like. A liquid acid can be also used as the solvent.

The reaction temperature is not critical, and the reaction can becarried out under cooling to heating.

Compound (9) thus obtained can be isolated or purified by knownseparation or purification means, such as concentration, concentrationin vacuo, solvent extraction, crystallization, recrystallization, phasetransfer, chromatography and the like, and can be converted to a saltsame as those exemplified for Compound (I).

Therefore, Compound (11) or a salt thereof can be prepared from Compound(10) or a salt thereof in a similar manner as described above. Suitablesalts of Compounds (10) and (11) may be the same as those exemplifiedfor Compound (I).

The nitrogen atom in Compound (6), (7), (8), (9), (10) or (11) may beprotected or deprotected, as necessary, in accordance with methods knownper se such as the methods described in Protective Groups in OrganicSynthesis, published by John Wiley and Sons (1980), and the like.

wherein

-   L₄ is a hydrogen atom or a protecting group, which is known per se,    such as tert-butoxycarbonyl as described in the above “optionally    protected amino” (see Protective Groups in Organic Synthesis,    published by John Wiley and Sons (1980), etc.); and-   R¹, X and Z are as defined above.    Amidation

Compound (12) or a reactive derivative thereof, or its salt is reactedwith Compound (13) or its salt to give an amidated compound (14).

Suitable reactive derivative of Compound (12) includes an acid halide,an acid anhydride and an activated ester.

The suitable example may be an acid chloride; an acid azide; a mixedacid anhydride with an acid such as substituted phosphoric acid (e.g.,dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, hologenated phosphoric acid, etc.),dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid,etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid(e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyricacid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g.,benzoic acid, etc.); a symmetrical acid anhydride; an activated amidewith imidazole, 4-substituted imidazole, dimethylpyrazole, triazole ortetrazole; an activated ester (e.g., cyanomethyl ester, methoxymethylester, dimethyliminomethyl [(CH₃)₂N⁺═CH—] ester, vinyl ester, propargylester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenylester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenylester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester,8-quinolyl thioester, etc.); or an ester with an N-hydroxy compound(e.g., N,N-dimethlhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide,1-hydroxy-6-chloro-1H-benzotriazole, etc.). These reactive derivativescan be optionally selected from them according to the kind of Compound(12) to be used.

Suitable salts of Compound (12) and a reactive derivative thereof aswell as Compound (13) may be the same as those exemplified for Compound(I).

Compound (12) and a reactive derivative thereof as well as Compound (13)or salts thereof may be commercially available or can be prepared inaccordance with the methods known per se (see Production Example 7).

The conventional amidation method may be employed in the presentinvention.

The reaction is usually carried out in a conventional solvent such asdichloromethane, methanol, ethanol, acetone, tetrahydrofuran,N,N-dimethylformamide, and any other organic solvent which does notadversely influence the reaction, or a mixture thereof.

The reaction is also preferably carried out in the presence of aconventional condensing agent such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,N,N′-dicyclohexylcarbodiimide,N,N′-carbonylbis(2-methylimidazole)triphenylphosphine, and an additivesuch as 1-hydroxybenzotriazole, 1-hydroxysuccinimide,3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine.

The reaction temperature is not critical, and the reaction can becarried out under cooling to heating.

Compound (14) thus obtained can be isolated or purified by knownseparation or purification means, such as concentration, concentrationin vacuo, solvent extraction, crystallization, recrystallization, phasetransfer, chromatography and the like, and can be converted to a saltsame as those exemplified for Compound (I).

The nitrogen atom in Compound (12), (13) or (14) may be protected ordeprotected, as necessary, in accordance with methods known per se suchas the methods described in Protective Groups in Organic Synthesis,published by John Wiley and Sons (1980), and the like.

The present invention is explained in more detail in the following byway of Production Examples and Examples, which are not to be construedas limitative.

The test compound used in the Example wasN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide(hereinafter Compound A) synthesized in Production Example 1.

PRODUCTION EXAMPLE 1

Step 1

A mixture of 3-chloro-2-oxopropyl acetate (5 g) and thiourea (2.5 g) inethanol (25 ml) was refluxed for 4 hours. The reaction mixture wascooled to ambient temperature and the resulting crystalline precipitatewas collected by filtration and washed with ethanol (20 ml) to give(2-amino-1,3-thiazol-4-yl)methyl acetate hydrochloride (3.5 g) as whitecrystals.

¹H-NMR (DMSO-d₆), δ (ppm): 2.07(3H, s), 4.92(2H, s), 6.87(1H, s).

MS: 173(M+H)⁺

Step 2

To a mixture of (2-amino-1,3-thiazol-4-yl)methyl acetate hydrochloride(56 g) and pyridine (45 g) in dichloromethane (560 ml) was added acetylchloride (23 g) over a period of 30 minutes at 5° C., and the reactionmixture was stirred for 10 minutes at the same temperature. The reactionmixture was poured into water (500 ml) and extracted with chloroform (1L). The organic layer was dried over sodium sulfate and concentrated invacuo. The residual solid was collected by filtration with isopropylether to give (2-(acetylamino)-1,3-thiazol-4-yl)methyl acetate (47 g) aswhite crystals.

¹H-NMR (CDCl₃), δ (ppm): 2.12(3H, s), 2.29(3H, s), 5.08(2H, s), 6.93(1H,s).

MS: 215(M+H)⁺

Step 3

A mixture of (2-(acetylamino)-1,3-thiazol-4-yl)methyl acetate (46 g) andpotassium carbonate (30 g) in methanol (640 ml) was stirred for 3 hoursat ambient temperature. The reaction mixture was concentrated in vacuo.The residue was diluted with chloroform, and the insoluble material wasfiltered off. The resulting solution was purified by flash columnchromatography on silica-gel with methanol/chloroform (1/99). Theresulted solid was collected by filtration with isopropyl ether to giveN-(4-(hydroxymethyl)-1,3-thiazol-2-yl)acetamide (35 g) as whitecrystals.

¹H-NMR (DMSO-d₆), δ (ppm): 2.12(3H, s), 4.44(2H, d, J=5.0 Hz), 5.20(1H,t, J=5.0 Hz), 6.88(1H, s), 12.02(1H, brs).

MS: 173(M+H)⁺

Step 4

N-(4-(Hydroxymethyl)-1,3-thiazol-2-yl)acetamide (2.8 g) was dissolved inmethanol (10 ml) and chloroform (200 ml). Then manganese (IV) oxide(28.3 g) was added to the solution under nitrogen atmosphere. Thereaction mixture was stirred at room temperature for 7 hours, andfiltered through a celite pad. The filtrate was concentrated in vacuo.The resulting solid was washed with ethyl ether to giveN-(4-formyl-1,3-thiazol-2-yl)acetamide (2.01 g) as an off-white solid.

mp. 195.5–199° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.17(3H, s), 8.28(1H, s), 9.79(1H, s),12.47(1H, brs).

Step 5

1-(Bromomethyl)-4-nitrobenzene (1.9 g), triphenylphosphine (2.31 g) andN,N-dimethylformamide (20 ml) were combined under nitrogen atmosphere.The reaction mixture was stirred at room temperature for 2.5 hours. Thenpotassium tert-butoxide (1.19 g) andN-(4-formyl-1,3-thiazol-2-yl)acetamide (1.5 g) were added and themixture was stirred at room temperature for 14 hours. The reactionmixture was poured into ice-water and extracted with ethyl acetate. Theorganic layer was washed with 1N-hydrochloric acid, water and saturatedsodium chloride solution, dried over anhydrous magnesium sulfate, andconcentrated in vacuo. The residue was purified by flash columnchromatography over silica gel with n-hexane/ethyl acetate (1:1)→(1:2)as an eluent, and triturated with ethyl ether to giveN-{4-[(Z)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (1.59 g)as a yellow solid.

mp. 155–157° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.13(3H, s), 6.64(1H, d, J=12.5 Hz), 6.71(1H,d, J=12.5 Hz), 7.18(1H, s), 7.79(2H, d, J=9.0 Hz), 8.17(2H, d, J=9.0Hz), 12.02(1H, brs).

MS: 290(M+H)⁺

Step 6

A mixture ofN-{4-[(Z)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (2 g) and10% palladium carbon (400 mg) in methanol (25 ml), tetrahydrofuran (25ml) and acetic acid (18 ml) was stirred under 4 atm hydrogen at ambienttemperature for 5 hours. The reaction mixture was filtered through acelite pad, and the filtrate was concentrated in vacuo. The residue wasdissolved in ethyl acetate. The organic solution was washed withsaturated sodium hydrogen carbonate solution and saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, andconcentrated in vacuo. The residue was purified by flash columnchromatography over silica gel with n-hexane/ethyl acetate (1:2)→ethylacetate as an eluent, and triturated with ethyl alcohol/ethyl ether togive N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (539.6 mg)as an off-white solid.

mp. 102.5–104° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.75(4H, brs), 4.82(2H, s),6.46(2H, d, J=8.5 Hz), 6.69(1H, s), 6.83(2H, d, J=8.5 Hz), 12.07(1H,brs).

MS: 262(M+H)⁺

Step 7

To a suspension ofN-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (26 g) inethanol (500 ml) was added 4N hydrogen chloride in ethyl acetate (25 ml)and cyanamide (6.3 g). The mixture was refluxed for 26 hours. Thereaction mixture was cooled to ambient temperature and poured into amixture of ethyl acetate (500 ml) and saturated sodium hydrogencarbonate solution (500 ml). The resulted precipitate was collected byfiltration and washed with water (300 ml) and ethanol (300 ml) to giveN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide(18 g) as white crystals.

¹H-NMR (DMSO-d₆), δ (ppm): 2.10(3H, s), 2.85(4H, s), 6.79(1H, s),6.83(2H, d, J=7 Hz), 7.10(2H, d, J=7 Hz).

MS: 304(M+H)⁺

PRODUCTION EXAMPLE 2 Synthesis ofN-(4-(2-(4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl)ethyl)-1,3-thiazol-2-yl)acetamide

N-(4-(2-(4-Aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (1.8 g)prepared in a similar manner according to Step 6 of Production Example1, 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole (918 mg), hydrochloricacid concentrate (0.57 ml) and 2-methoxyethanol (28 ml) were combinedunder nitrogen atmosphere, and stirred at 120° C. for 10 hours. Aftercooled to room temperature, the reaction mixture was concentrated invacuo. The residue was dissolved in tetrahydrofuran/water, and madebasic with aqueous potassium carbonate. The mixture was extracted withethyl acetate. The organic layer was dried over magnesium sulfate, andevaporated in vacuo. The residue was purified by flash columnchromatography over silica gel with chloroform/methanol (30:1→20:1) asan eluent, and triturated with ethyl acetate to giveN-(4-(2-(4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl)ethyl)-1,3-thiazol-2-yl)acetamide(484.7 mg) as an off-white solid.

mp. 218–219.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.84(4H, s), 3.26(2H, t, J=7.5Hz), 3.35(2H, t, J=7.5 Hz), 4.02(1H, brs), 6.71(1H, brs), 7.05(2H, d,J=8.5 Hz), 7.51(1H, brs), 9.25(1H, brs), 12.10(1H, brs).

MS: 347(M+H)⁺

PRODUCTION EXAMPLE 3 Synthesis ofN-(4-{(E)-2-[4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl]ethenyl}-1,3-thiazol-2-yl)acetamide

Step 1

A mixture of 4-nitrobenzyl bromide (6.35 g), triphenylphosphine (7.71 g)and N,N-dimethylformamide (50 ml) was stirred for 5 hours at roomtemperature. To the mixture were added potassium butoxide (3.96 g), andthen N-(4-formyl-1,3-thiazol-2-yl)acetamide (5.0 g) prepared in asimilar manner according to Step 4 of Production Example 1, and themixture was stirred for 13 hours at the same temperature. The reactionmixture was poured into ethyl acetate (200 ml) and water (200 ml). Theorganic layer was washed with water (20 ml), dried over sodium sulfateand concentrated in vacuo. The crystalline residue was collected andwashed with 30% ethyl acetate/diisopropyl ether to giveN-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (7.8 g).

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 7.29(1H, d, J=16 Hz), 7.48(1H,d, J=16 Hz), 7.88(2H, d, J=7 Hz), 8.22(2H, d, J=7 Hz).

MS (M+H)=290

Step 2

A mixture ofN-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (250 mg),palladium on carbon (25 mg) and methanol (2.5 ml) was stirred underhydrogen atmosphere for 2 hours at ambient temperature. The catalyst wasfiltered off and the filtrate was concentrated in vacuo. The crystallineresidue was collected and washed with isopropyl ether to giveN-{4-[(E)-2-(4-aminophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (160 mg).

¹H-NMR (DMSO-d₆), δ (ppm): 2.14(3H, s), 5.33(2H, s), 6.55(2H, d, J=7Hz), 6.82(1H, d, J=10 Hz), 6.44(1H, s), 7.09(1H, d, J=10 Hz), 7.20(2H,d, J=7 Hz).

MS: 260(M+H)⁺

Step 3

A mixture ofN-{4-[(E)-2-(4-aminophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (200 mg),2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole (103 mg), hydrochrolic acid(0.064 ml) and 2-methoxyethanol (2 ml) was stirred at 120° C. for 8hours. The reaction mixture was concentrated in vacuo. The residue waspurified by silica-gel flash column chromatography with hexane:ethylacetate (3:1) as an eluent. The crystalline residue was collected andwashed with ethyl acetate to giveN-(4-{(E)-2-[4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl]ethenyl}-1,3-thiazol-2-yl)acetamide(150 mg).

¹H-NMR (CDCl₃), δ (ppm): 2.27(3H, s), 3.33–3.40(2H, m), 3.57–3.65(2H,m), 6.94(1H, s), 7.05(1H, d, J=12 Hz), 7.29(1H, d, J=12 Hz), 7.30(2H, d,J=7 Hz), 7.57(2H, d, J=7 Hz).

MS: 345(M+H)⁺

PRODUCTION EXAMPLE 4 Synthesis of methylN-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)imidothiocarbamatehydriodide

Step 1

To an ice-cold solution ofN-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (300 mg)prepared in a similar manner according to Step 6 of Production Example 1in acetone (5 ml) was added benzoyl isothiocyanate (187 mg) and themixture was refluxed for 2 hours. The reaction mixture was cooled to 0°C. The precipitated crystals were filtered and washed with ice-coldacetone to giveN-{4-[2-(4-{[(benzoylamino)carbonothioyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide(359 mg).

¹H-NMR (CDCl₃), δ (ppm): 2.25(3H, s), 2.90–3.05(4H, m), 6.51(1H, s),7.21(2H, d, J=7 Hz), 7.50–7.70(5H, m), 7.89(2H, d, J=7 Hz), 9.03(1H, s),9.12(1H, s).

MS (M+H)=425

Step 2

A mixture ofN-{4-[2-(4-{[(benzoylamino)carbonothioyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide(200 mg), 6N aqueous sodium hydroxide (0.19 ml) and ethanol (2 ml) wasstirred at 60° C. for 2 hours. The reaction mixture was cooled toambient temperature and neutralized with 1N hydrochloric acid (1.2 ml).The precipitated crystals were filtered and washed with water to giveN-[4-(2-{4-[(aminocarbonothioyl)amino]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide(120 mg).

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.88(4H, s), 6.75(1H, s),7.15(2H, d, J=7 Hz), 7.27(2H, d, J=7 Hz), 9.60(1H, s).

MS (M+H)=321

Step 3

A mixture ofN-[4-(2-{4-[(aminocarbonothioyl)amino]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide(100 mg), methyl iodide (0.023 ml) and methanol (2 ml) was refluxed for3 hours. The reaction mixture was concentrated in vacuo. The residue wasdiluted with ethyl acetate and stirred for 30 minutes. The precipitatedcrystals were filtered and washed with ethyl acetate to give methylN-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)imidothiocarbamatehydriodide (130 mg).

¹H-NMR (DMSO-d₆), δ (ppm): 2.13(3H, s), 2.68(3H, s), 2.87–3.05(4H, m),6.75(1H, s), 7.24(2H, d, J=7 Hz), 7.35(2H, d, J=7 Hz).

MS (M+H)=463

PRODUCTION EXAMPLE 5 Synthesis ofN-(4-{2-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide

A mixture of N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide(65 mg) prepared in a similar manner according to Step 6 of ProductionExample 1, ethyl2-(methylsulfanyl)-4,5-dihydro-1H-imidazole-1-carboxylate (56 mg),acetic acid (0.1 ml), ethanol (0.9 ml) was stirred at 65° C. for 6hours, and then refluxed for 5 hours. The reaction mixture was pouredinto ethyl acetate (5 ml) and saturated aqueous sodium bicarbonate. Theprecipitated solid was filtered, and the solid was dissolved in 50%methanol/chloroform. The insoluble materials were filtered off and thefiltrate was concentrated in vacuo. The solid residue was collected andwashed with ethyl acetate to giveN-(4-{2-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-ethyl}-1,3-thiazol-2-yl)acetamide(40 mg).

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.72(4H, s), 3.33(4H, s),6.73(1H, s), 6.85–7.08(4H, m).

MS (M+H)=330

PRODUCTION EXAMPLE 6 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}-2-methylpropanamide

Step 1

To an ice-cold mixture of ethyl 2-amino-1,3-thiazole-4-carboxylate (2 g)prepared in a similar manner according to Step 1 of the followingProduction Example 7, pyridine (1.3 ml) and dichloromethane (20 ml) wasadded isobutyryl chloride (0.91 ml) and stirred for 30 minutes. To themixture was added saturated aqueous hydrogen bicarbonate (30 ml), andthe organic layer was separated, dried over sodium sulfate andconcentrated in vacuo. The crystalline residue was collected and washedwith ethyl acetate to give ethyl2-(isobutyrylamino)-1,3-thiazole-4-carboxylate (1.34 g).

¹H-NMR (CDCl₃), δ (ppm): 1.30(6H, d, J=7 Hz), 1.40(3H, t, J=7 Hz),2.57–2.73(1H, m), 4.41(2H, q, J=7 Hz), 7.83(1H, s), 8.98(1H, s).

MS: 243(M+H)⁺

Step 2

To a mixture of ethyl 2-(isobutyrylamino)-1,3-thiazole-4-carboxylate(1.4 g) and tetrahydrofuran (28 ml) was added lithium borohydride (252mg) portionwise, and the mixture was refluxed for 6 hours. The reactionmixture was cooled to 0° C., quenched with methanol (5 ml) andconcentrated in vacuo. The residue was suspended with 10%methanol/chloroform (100 ml), and the insoluble materials were filteredoff. The filtrate was purified by flash column chromatography onsilica-gel with 5% methanol/chloroform as an eluent. The crystallineresidue was collected and washed with diisopropyl ether to giveN-[4-(hydroxymethyl)-1,3-thiazol-2-yl]-2-methylpropanamide (1.0 g).

¹H-NMR (CDCl₃), δ (ppm): 1.32(6H, d, J=5 Hz), 2.58–2.73(1H, m), 4.68(2H,s), 6.82(1H, s).

MS (M+H)=200

Step 3

A mixture of N-[4-(hydroxymethyl)-1,3-thiazol-2-yl]-2-methylpropanamide(520 mg), manganese (IV) oxide (2.26 g), methanol (0.5 ml) andchloroform (5 ml) was stirred at ambient temperature for 18 hours. Thereaction mixture was filtered through a celite pad, and the filtrate wasconcentrated in vacuo. The crystalline residue was collected and washedwith diisopropyl ether to giveN-(4-formyl-1,3-thiazol-2-yl)-2-methylpropanamide (365 mg).

¹H-NMR (CDCl₃), δ (ppm): 1.13(6H, d, J=5 Hz), 2.60–2.77(1H, m), 7.86(1H,s).

MS (M+H)=199

Step 4

A mixture of 4-nitrobenzyl bromide (381 mg), triphenylphosphine (463 mg)and N,N-dimethylformamide (3 ml) was stirred for 5 hours at roomtemperature. To the mixture were added potassium butoxide (238 mg) andthen N-(4-formyl-1,3-thiazol-2-yl)-2-methylpropanamide (350 mg), and themixture was stirred for 13 hours at the same temperature. The reactionmixture was poured into ethyl acetate (20 ml) and water (20 ml). Theorganic layer was washed with water (20 ml), dried over sodium sulfateand concentrated in vacuo. The crystalline residue was collected andwashed to give2-methyl-N-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}propanamide(360 mg).

¹H-NMR (CDCl₃), δ (ppm): 1.25(6×⅔H, d, J=5 Hz), 1.30(6×⅓H, d, J=5 Hz),2.50–5.70(1H, m), 6.63(1H, s), 6.79(1×⅔H, s), 6.97(1×⅔H, s), 7.14(1×⅓H,d, J=12 Hz), 7.33(1×⅓H, d, J=12 Hz), 7.53(2×⅔H, d, J=7 Hz), 7.62(2×⅓H,d, J=7 Hz), 8.13(2×⅔H, d, J=7 Hz), 8.22(2×⅓H, d, J=7 Hz).

MS (M+H)=318

Step 5

A mixture of2-methyl-N-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}propanamide(333 mg), palladium on carbon (33 mg), acetic acid (1 ml), methanol (2ml) and tetrahydrofuran (2 ml) was stirred under hydrogen atmosphere (4atm) at ambient temperature for 5 hours. The catalyst was filtered off,and the filtrate was concentrated in vacuo. The residue was purified byflash column chromatography on silica gel with 5% methanol/ethyl acetateas an eluent. The solid residue was collected and washed withdiisopropyl ether to giveN-{4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-yl}-2-methylpropanamide (260mg).

¹H-NMR (CDCl₃), δ (ppm): 1.38(6H, d, J=5 Hz), 2.57–2.73(1H, m),2.39–2.43(4H, m), 6.45(1H, s), 6.62(2H, d, J=7 Hz), 6.97(2H, d, J=7 Hz).

MS (M+H)=290

Step 6

The title compound was prepared in a similar manner according to Step 7of Production Example 1.

¹H-NMR (DMSO-d₆), δ (ppm): 1.01(6H, d, J=5 Hz), 2.62–2.78(1H, m),2.83(4H, s), 6.72(2H, d, J=7 Hz), 6.75(1H, s), 7.04(2H, d, J=7 Hz).

MS (M+H)=332

PRODUCTION EXAMPLE 7 Synthesis of2-(acetylamino)-N-(4-{[amino(imino)methyl]amino}phenyl)-1,3-thiazole-4-carboxamide

Step 1

A mixture of ethyl 3-bromo-2-oxopropanoate (100 g), thiourea (39 g) andethanol (500 ml) was refluxed for 2 hours. The reaction mixture wasconcentrated in vacuo. The crystalline residue was collected and washedwith ethyl acetate to give ethyl 2-amino-1,3-thiazole-4-carboxylatehydrobromide (116 g).

¹H-NMR (DMSO-d₆), δ (ppm): 1.28(3H, t, J=7 Hz), 4.26(2H, q, J=7 Hz),7.60(1H, s).

Step 2

To an ice-cold mixture of ethyl 2-amino-1,3-thiazole-4-carboxylatehydrobromide (80 g), pyridine (52.5 g) and dichloromethane (800 ml) wasadded acetyl chloride (27.3 g) dropwise at 0° C., and the mixture wasstirred for 30 minutes at the same temperature. The reaction mixture waswashed with water (500 ml), dried over sodium sulfate and concentratedin vacuo. The crystalline residue was collected and washed with ethylacetate to give ethyl 2-(acetylamino)-1,3-thiazole-4-carboxylate (60 g).

¹H-NMR (DMSO-d₆), δ (ppm): 1.29(3H, t, J=7 Hz), 2.15(3H, s), 4.27(2H, q,J=7 Hz), 8.03(1H, s).

MS (M+H)=215

Step 3

A mixture of ethyl 2-(acetylamino)-1,3-thiazole-4-carboxylate (2 g), 2Nsodium hydroxide (7 ml) and methanol (13 ml) was stirred at ambienttemperature for 5 hours. The reaction mixture was neutralized by 1Nhydrochloric acid (14 ml). The precipitated crystals were filtered andwashed with water to give 2-(acetylamino)-1,3-thiazole-4-carboxylic acid(1.3 g).

¹H-NMR (DMSO-d₆), δ (ppm): 2.14(3H, s), 7.94(1H, s).

Step 4

A mixture of 2-(acetylamino)-1,3-thiazole-4-carboxylic acid (500 mg),tert-butyl 4-aminophenylcarbamate (615 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (566 mg),1-hydroxybenzotriazole (399 mg) and dichloromethane (5 ml) was stirredat ambient temperature for 3 hours. The reaction mixture was washed withsaturated aqueous sodium hydrogen bicarbonate, and the organic layer wasconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel with 3% methanol/chloroform as an eluent.The crystalline residue was collected and washed with ethyl acetate togive tert-butyl4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl}amino)phenylcarbamate(580 mg).

¹H-NMR (DMSO-d₆), δ (ppm): 1.48(9H, s), 2.18(3H, s), 7.42(2H, d, J=7Hz), 7.61(2H, d, J=7 Hz), 7.91(1H, s), 9.32(1H, s), 9.63(1H, s).

MS (M+H)=377

Step 5

To a solution of tert-butyl4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl}amino)phenylcarbamate (85mg) in methanol (1 ml) was added 4N hydrogen chloride in ethyl acetate(1 ml), and the mixture was stirred at ambient temperature for 1 hour.The reaction mixture was concentrated in vacuo. The solid residue wascollected and washed with ethyl acetate to give2-(acetylamino)-N-(4-aminophenyl)-1,3-thiazole-4-carboxamidehydrochloride (70 mg).

¹H-NMR (DMSO-d₆), δ (ppm): 2.15(3H, s), 7.42(2H, d, J=7 Hz), 7.37(2H, d,J=7 Hz), 7.41(1H, s).

MS (M+H)=313

Step 6

A mixture of2-(acetylamino)-N-(4-aminophenyl)-1,3-thiazole-4-carboxamidehydrochloride (70 mg), cyanamide (11 mg) and 2-methoxyethanol (2 ml) wasstirred at 100° C. for 72 hours. The reaction mixture was concentratedin vacuo. To the residue was added ethyl acetate (5 ml) and saturatedaqueous sodium hydrogen bicarbonate (5 ml). The precipitated solid wasfiltered and washed with ethyl acetate and water to give2-(acetylamino)-N-(4-{[amino(imino)methyl]amino}phenyl)-1,3-thiazole-4-carboxamide(45 mg).

¹H-NMR (DMSO-d₆), δ (ppm): 2.18(3H, s), 7.60–7.88(4H, br), 7.95(1H, s).

MS (M+H)=319

PRODUCTION EXAMPLE 8 Synthesis ofN-(4-{2-[4-(ethanimidoylamino)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide

N-(4-(2-(4-Aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (100 mg)prepared in a similar manner according to Step 6 of Production Example1, methyl ethanimidothioate hydriodide (166 mg) and methanol (3 ml) werecombined, and refluxed for 1.5 hours. After cooled to room temperature,the mixture was concentrated in vacuo. The residue was purified by flashcolumn chromatography over NH silica gel with chloroform/methanol(20:1→10:1) as an eluent to giveN-(4-{2-[4-(ethanimidoylamino)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide(165 mg) as a pale yellow amorphous substance.

¹H-NMR (CDCl₃), δ (ppm): 2.03(3H, brs), 2.19(3H, s), 2.92(4H, s),6.47(1H, s), 6.78(2H, d, J=8.0 Hz), 7.08(2H, d, J=8.0 Hz).

MS: 303(M+H)⁺

PRODUCTION EXAMPLE 9 Synthesis ofN-[4-(2-{4-[amino(imino)methyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamidehydrochloride

Step 1

4-(Bromomethyl)benzonitrile (1.73 g), triphenylphosphine (2.31 g) andN,N-dimethylformamide (20 ml) were combined under nitrogen atmosphere.The reaction mixture was stirred at room temperature for 1.5 hours. Thenpotassium tert-butoxide (1.19 g) andN-(4-formyl-1,3-thiazol-2-yl)acetamide (1.5 g) prepared in a similarmanner according to Step 4 of Production Example 1 were added to themixture, and stirred at room temperature for 3 hours. The reactionmixture was poured into ice-water, and extracted with ethyl acetate. Theorganic layer was washed with 1N-hydrochloric acid, water and saturatedsodium chloride solution, dried over anhydrous magnesium sulfate, andconcentrated in vacuo. The residue was purified by flash columnchromatography over silica gel with n-hexane/ethyl acetate (1:1) as aneluent, and triturated with ethyl ether to give a mixture ofN-{4-[(Z)-2-(4-cyanophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide andN-{4-[(E)-2-(4-cyanophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (Z:E=3:1)(1.63 g) as a pale yellow solid.

mp. 175–176° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.13(3H×¾, s), 2.16(3H×¼, s), 6.59(1H×¾, d,J=13.0 Hz), 6.65(1H×¾, d, J=13.0 Hz), 7.11(1H×¾, s), 7.24(1H×¼, d,J=16.0 Hz), 7.28(1H×¼, s), 7.40(1H×¼, d, J=16.0 Hz), 7.65(2H×¾, d, J=8.5Hz), 7.74(2H×¼, d, J=8.5 Hz), 7.75(2H×¾, d, J=8.5 Hz), 7.83(2H×¼, d,J=8.5 Hz), 12.00(1H, brs).

MS: 270(M+H)⁺

Step 2

A mixture ofN-{4-[(Z)-2-(4-cyanophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide andN-{4-[(E)-2-(4-cyanophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (Z:E=3:1)(1.5 g), 10% palladium on carbon (323 mg), methanol (20 ml),tetrahydrofuran (10 ml) and acetic acid (5 ml) were combined. Thereaction mixture was stirred under 4 atm hydrogen at ambient temperaturefor 9 hours, and filtered through a celite pad. The filtrate wasconcentrated in vacuo. The residue was purified by flash columnchromatography over silica gel with n-hexane/ethyl acetate(1:1)→chloroform/methanol (30:1) as an eluent, and triturated with ethylether to give N-{4-[2-(4-cyanophenyl)ethyl]-1,3-thiazol-2-yl}acetamide(1.18 g) as a colorless solid.

mp. 205–206.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.90(2H, t, J=8.0 Hz), 3.01(2H,t, J=8.0 Hz), 6.73(1H, s), 7.40(2H, d, J=8.0 Hz), 7.74(2H, d, J=8.0 Hz),12.09(1H, brs).

MS: 272(M+H)⁺

Step 3

N-{4-[2-(4-Cyanophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (600 mg) wasdissolved in ethanol (5 ml) and chloroform (5 ml), and then hydrochloricacid gas was bubbled at 0° C. for 5 minutes with stirring. The reactionmixture was stood for 15 hours, and concentrated in vacuo. The residualsolid was washed with diethyl ether to give ethyl4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzenecarboximidoatehydrochloride (924.7 mg) as a pale green solid.

mp. 129–130° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.48(3H, t, J=7.0 Hz), 2.12(3H, s), 2.95(2H,t, J=8.0 Hz), 3.07(2H, t, J=8.0 Hz), 4.61(2H, q, J=7.0 Hz), 6.72(1H, s),7.46(2H, d, J=8.5 Hz), 8.02(2H, d, J=8.5 Hz), 11.25(1H, brs), 11.98(1H,brs), 12.11(1H, brs).

MS: 318(M+H)⁺ free

Step 4

Ethyl 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzenecarboximidoatehydrochloride (300 mg) was dissolved in ethanol (6 ml). Then ammoniumchloride (68 mg) and ammonia in methanol (1 ml) were added to thesolution. The reaction mixture was refluxed for 5 hours under nitrogenatmosphere. After cooled to room temperature, the suspension wasfiltered in vacuo. The filtrate was concentrated in vacuo, and theresidue was solidified with ethanol/diethyl ether to giveN-[4-(2-{4-[amino(imino)methyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamidehydrochloride (234 mg) as a colorless solid.

mp. 229.5–231° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.12(3H, s), 2.94(2H, t, J=8.0 Hz), 3.06(2H,t, J=8.0 Hz), 6.75(1H, s), 7.44(2H, d, J=8.5 Hz), 7.76(2H, d, J=8.5 Hz),12.10(1H, brs).

MS: 289(M+H)⁺ free

PRODUCTION EXAMPLE 10 Synthesis ofN-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)-2-{[amino(imino)methyl]amino}acetamidehydrochloride

Step 1

A mixture of N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide(100 mg) prepared in a similar manner according to Step 6 of ProductionExample 1, ((tert-butoxycarbonyl)amino)acetic acid (74 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg),1-hydroxybenzotriazole (57 mg) and dichloromethane (5 ml) was stirred atambient temperature for 3 hours. The reaction mixture was washed withsaturated aqueous sodium hydrogen bicarbonate, and the organic layer wasconcentrated in vacuo. The residue was purified by flash columnchromatography on silica-gel with 3% methanol/chloroform as an eluent.The crystalline residue was collected and washed with ethyl acetate togive tert-butyl2-[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]-2-oxoethylcarbamate(580 mg).

¹H-NMR (CDCl₃), δ (ppm): 1.47(9H, s), 2.25(3H, s), 2.92(4H, s), 3.92(2H,d, J=5 Hz), 6.46(1H, s), 7.10(2H, d, J=7 Hz), 7.38(2H, d, J=7 Hz).

MS (M+H)=419

Step 2

To a solution of tert-butyl2-[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]-2-oxoethylcarbamate(100 mg) in ethyl acetate (1 ml) was added 4N hydrogen chloride in ethylacetate (1 ml), and the mixture was stirred at ambient temperature for103 hours. The precipitated solid was filtered and washed with ethylacetate to giveN-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)-2-aminoacetamidehydrochloride (80 mg).

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.87(4H, s), 6.70(1H, s),7.17(2H, d, J=7 Hz), 7.49(2H, d, J=7 Hz).

MS (M+H)=319

Step 3

The title compound was prepared in a similar manner according to Step 7of Production Example 1.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.80–2.95(4H, m), 3.76(2H, s),6.70(1H, s), 7.26(2H, d, J=7 Hz), 7.49(2H, d, J=7 Hz), 8.16(2H, s).

MS (M+H)=361

PRODUCTION EXAMPLE 11 Synthesis ofN-{4-[4-(2-{[amino(imino)methyl]amino}ethyl)phenyl]-1,3-thiazol-2-yl}acetamidehydrochloride

Step 1

Aluminium chloride (1.63 g) was dissolved in 1,2-dichloroethane (15 mL).Chloroacetylchloride (0. 732 mL) was added to the mixture at 0° C., andstirred additionally for 20 minutes, then N-(2-phenylethyl)acetamide (1g) in 1,2-dichloroethane (5 mL) was added dropwise. The mixture wasstirred for 1 hour at room temperature, and then poured into ice water.The mixture was extracted with chloroform, washed with water andsaturated sodium chloride solution, dried over sodium sulfate andconcentrated in vacuo. The solid was washed with ethyl acetate and ethylether, and dried in vacuo to giveN-{2-[4-(2-chloroacetyl)phenyl]ethyl}acetamide as a white powder (1.18g, 80.4%).

¹H-NMR (300 MHz, DMSO-d₆), δ (ppm): 7.92(2H, d, J=6 Hz), 7.34(2H, d, J=6Hz), 5.66(1H, br), 4.70(2H, s), 3.55–3.60(2H, m), 2.90–2.94(2H, m),1.98(3H, s).

Step 2

N-{2-[4-(2-Chloroacetyl)phenyl]ethyl}acetamide (1.06 g) and thiourea(505 mg) were dissolved in ethanol (20 mL). The mixture was refluxed for1 hour and allowed to cool to room temperature. The white solid wascollected with filtration and washed with ethanol to giveN-{2-[4-(2-amino-1,3-thiazol-4-yl)phenyl]ethyl}acetamide hydrochloride(1.19 g, 90.4%).

MS m/z 262 (M++1).

¹H-NMR (300 MHz, DMSO-d₆), δ (ppm): 7.93–7.96(2H, m), 7.69(2H, d, J=6Hz), 7.30(2H, d, J=6 Hz), 7.16(1H, s), 3.23–3.30(2H, m), 2.70–2.76(2H,m), 1.78 (3H, s).

Step 3

N-{2-[4-(2-Amino-1,3-thiazol-4-yl)phenyl]ethyl}acetamide (0.6 g) wasdissolved in ethanol (10 mL) and hydrochloric acid concentrate (10 mL).The mixture was refluxed for 5 hours. The solvent was evaporated invacuo. The residue was washed with ethyl ether to give4-[4-(2-aminoethyl)phenyl]-1,3-thiazol-2-amine dihydrochrolide (0.5 g,84.6%).

MS m/z 220 (M++1).

¹H-NMR (300 MHz, DMSO-d₆), δ (ppm): 8.15(3H, br), 7.78(2H, d, J=6 Hz),7.39(2H, d, J=6 Hz), 7.24(1H, s), 3.03–3.10(2H, m), 2.90–2.98(2H, m).

Step 4

4-[4-(2-Aminoethyl)phenyl]-1,3-thiazol-2-amine dihydrochrolide (0.45 g)was dissolved in 1,4-dioxane (10 mL), water (3 mL) and 1N sodiumhydroxide solution (3.1 mL). Di-tert-butyl dicarbonate (336 mg) wasadded at 0° C. The mixture was stirred at room temperature overnight,then extracted with ethyl acetate, washed with water and saturatedsodium chloride solution, dried over sodium sulfate and concentrated invacuo. The solid was washed with ethyl ether, and dried in vacuo to givetert-butyl {2-[4-(2-amino-1,3-thiazol-4-yl)phenyl]ethyl}carbamate as awhite solid (311 mg, 63.2%).

MS m/z 320 (M++1).

¹H-NMR (300 MHz, DMSO-d₆), δ (ppm): 7.69(2H, d, J=6 Hz), 7.18(2H, d, J=6Hz), 7.02(2H, br), 7.69(1H, s), 3.10–3.27(2H, m), 2.65–2.72(2H, m),1.37(9H, s).

Step 5

tert-Butyl {2-[4-(2-amino-1,3-thiazol-4-yl)phenyl]ethyl}carbamate (290mg) was dissolved in dichloromethane (5 mL), then acetic anhydride(0.103 mL), 4-dimethylaminopyridine (10 mg) and pyridine (0.147 mL) wereadded. The mixture was stirred overnight. The mixture was extracted withchloroform, washed with water and saturated sodium chloride solution,dried over sodium sulfate and concentrated in vacuo. The solid waswashed with ethyl ether, and dried in vacuo to give tert-butyl(2-{4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl)carbamate as awhite solid (280 mg, 85.3%).

MS m/z 362 (M++1).

¹H-NMR (300 MHz, DMSO-d₆), δ (ppm): 7.80(2H, d, J=6 Hz), 7.53(1H, s),7.24(2H, d, J=6 Hz), 6.90(1H, m), 3.12–3.18(2H, m), 2.16–2.63(2H, m),2.16(3H, s), 1.37(9H, s).

Step 6

tert-Butyl(2-{4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl)carbamate (250 mg)was dissolved in ethyl acetate (4 mL) and 4 N hydrogen chloride in ethylacetate (2 mL). The solvent was evaporated in vacuo. The solid waswashed with ethyl acetate and ethyl ether to giveN-{4-[4-(2-aminoethyl)phenyl]-1,3-thiazol-2-yl}acetamide hydrochloride(220 mg, 106%).

MS m/z 262 (M++1).

¹H-NMR (300 MHz, DMSO-d₆), δ (ppm): 8.05(3H, br), 7.85(2H, d, J=6 Hz),7.58(1H, s), 7.32(2H, d, J=6 Hz), 3.12–3.18(2H, m), 2.88–2.94(2H, m),2.16(3H, s).

Step 7

N-{4-[4-(2-Aminoethyl)phenyl]-1,3-thiazol-2-yl}acetamide hydrochloride(200 mg) and diisopropylethylamine (0.175 mL) were dissolved intetrahydrofuran (5 mL). The mixture was stirred at room temperatureovernight, then evaporated in vacuo. The residue was purified withsilica gel chromatography (5% methanol/chloroform) to give di-tert-butyl{[(2-{4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl)amino]methylidene}-biscarbamate(268 mg, 79.2%).

MS m/z 504 (M++1).

Step 8

Di-tert-butyl{[(2-{4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl)amino]methylidene}biscarbamate(268 mg, 79.2%) (170 mg) was dissolved in 4 N hydrogen chloride in1,4-dioxane (5 mL). The mixture was stirred at room temperature for 2days, and then evaporated in vacuo. The residue was washed with ethylether, dried in vacuo to giveN-{4-[4-(2-{[amino(imino)methyl]amino}ethyl)phenyl]-1,3-thiazol-2-yl}acetamidehydrochloride (50 mg, 43.6%).

MS m/z 304 (M++1).

¹H-NMR (300 MHz, DMSO-d₆), δ (ppm): 7.83(2H, d, J=8 Hz), 7.62–7.66(1H,m), 7.56(1H, s), 7.34(2H, d, J=8 Hz), 3.37–3.45(2H, m), 2.78–2.85(2H,m), 2.16(3H, s).

PRODUCTION EXAMPLE 12 Synthesis ofN-(4-{2-[4-(aminomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide

Step 1

To a mixture ofN-(4-{2-[4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (50mg) prepared in a similar manner according to Step 3 of the followingProduction Example 16, carbon tetrabromide (72 mg) and dichloromethane(1 ml) was added triphenylphosphine (71 mg), and the mixture was stirredat ambient temperature for 1 hour. The reaction mixture was purified byflash column chromatography on silica gel with 1% methanol/chloroform asan eluent. The crystalline residue was collected and washed withdiisopropyl ether to giveN-(4-{2-[4-(bromomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (48mg).

¹H-NMR (CDCl₃), δ (ppm): 2.25(3H, s), 2.85–3.03(4H, m), 4.49(2H, s),6.48(1H, s), 7.13(2H, d, J=7 Hz), 7.30(2H, d, J=7 Hz).

MS (M+H)=339

Step 2

To a mixture ofN-(4-{2-[4-(bromomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (100mg), tetrahydrofuran (2 ml) and N,N-dimethylformamide (2 ml) was addedsodium diformylimide (42 mg), and the mixture was stirred at ambienttemperature for 1 hour. The reaction mixture was diluted with water (3ml), and the precipitated solid was filtered and washed with water togiveN-[4-(2-{4-[(diformylamino)methyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide(80 mg).

¹H-NMR (CDCl₃), δ (ppm): 2.23(3H, s), 2.83–3.00(4H, m), 4.72(2H, s),6.48(1H, s), 7.10(2H, d, J=7 Hz), 7.38(2H, d, J=7 Hz).

MS (M+H)=318

Step 3

To a solution ofN-[4-(2-{4-[(diformylamino)methyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide(56 mg) in methanol (0.5 ml) was added 4N hydrogen chloride in ethylacetate (0.5 ml), and the mixture was stirred at ambient temperature for1 hour. The reaction mixture was concentrated in vacuo. The residue wasseparated between chloroform (5 ml) and saturated aqueous sodiumhydrogen bicarbonate (5 ml), and the aqueous layer was extracted withchloroform (5 ml). The organic layer was dried over sodium sulfate andconcentrated in vacuo to giveN-(4-{2-[4-(aminomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (50mg).

¹H-NMR (DMSO-d₆), δ (ppm): 2.12(3H, s), 2.80–3.00(4H, m), 3.92–4.05(2H,m), 6.72(1H, s), 7.24(2H, d, J=7 Hz), 7.37(2H, d, J=7 Hz).

MS (M+H)=276

PRODUCTION EXAMPLE 13 Synthesis of ethyl4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-ylcarbamatehydrochloride

Step 1: ethyl 4-(hydroxymethyl)-1,3-thiazol-2-ylcarbamate

A mixed solution of ethyl 4-(chloromethyl)-1,3-thiazol-2-ylcarbamate(500 mg) in 1,4-dioxane (5 ml) and water (10 ml) was refluxed withstirring for 3.5 hours. After cooling, it was concentrated under reducedpressure. The mixture was partitioned between ethyl acetate and water.The organic phase was separated, washed with brine, dried over magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (10 g) using a mixedsolvent of hexane and ethyl acetate (2:1). The fractions containing theobjective compound were collected and evaporated under reduced pressureto give colorless syrup (450 mg, 98.2%).

MS (ES+); 203 (M+H)⁺

¹H-NMR (CDCl₃), δ (ppm): 1.39(3H, t, J=7.0 Hz), 4.39(2H, q, J=7.0 Hz),4.61(2H, s), 6.80(1H, s).

Step 2: ethyl 4-formyl-1,3-thiazol-2-ylcarbamate

To a mixed solution of ethyl 4-(hydroxymethyl)-1,3-thiazol-2-ylcarbamate(446 mg) in chloroform (30 ml) and methanol (3 ml) was added portionwisemanganese (IV) oxide chemicals treated (1.92 g) at room temperature.After the mixture was stirred at the same temperature for 2 hours, thentreated manganese (IV) oxide chemicals (250 mg) was added again to thesolution, and it was stirred at 50° C. for 3 hours. Manganese (IV) oxidewas removed by filtration and the filtrate was concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (10 g) using a mixed solvent of hexane and ethyl acetate(4:1). The fractions containing the objective compound were collectedand evaporated under reduced pressure to give colorless powder (470 mg,106.4%).

¹H-NMR (CDCl₃), δ (ppm): 1.36(3H, t, J=7.0 Hz), 4.34(2H, q, J=7.0 Hz),7.83(1H, s), 9.54(1H, br), 9.88(1H, s).

Step 3

Ethyl 4-[2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-ylcarbamate (E-Zmixture) was obtained in a similar manner according to Step 5 ofProduction Example 1.

¹H-NMR (CDCl₃) (cis-trans product mixture), δ (ppm): 1.20–1.40(3H, m),4.20–4.40(2H, m), 6.60, 6.66(1.2H, ABq, J=13 Hz), 6.74(0.6H, s),6.94(0.4H, s), 7.12, 7.30(0.8H, ABq, J=16 Hz), 7.53(1.2H, d, J=8.9 Hz),7.61(0.8H, d, J=8.9 Hz), 8.11(1.2H, d, J=8.9 Hz), 8.22(0.8H, d, J=8.9Hz).

Step 4

Ethyl 4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-ylcarbamate was obtainedin a similar manner according to Step 6 of Production Example 1.

MS (ES+); 292(M+H)⁺

¹H-NMR (DMSO-d₆), δ (ppm): 1.24(3H, t, J=7.1 Hz), 2.65–2.80(4H, m),4.18(2H, q, J=7.1 Hz), 4.82(2H, br), 6.46(2H, d, J=8.5 Hz), 6.69(1H, s),6.84(2H, d, J=8.5 Hz).

Step 5

Ethyl4-[2-(4-{N′,N″-bis(tert-butoxycarbonyl)-[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-ylcarbamatewas obtained in a similar manner according to Step 3 of the followingProduction Example 14.

¹H-NMR (CDCl₃), δ (ppm): 1.29(3H, t, J=7.0 Hz), 1.40–1.70(18H, m),2.94(4H, s), 4.27(2H, q, J=7.0 Hz), 6.45(1H, s), 7.12(2H, d, J=8.4 Hz),7.48(2H, d, J=8.4 Hz), 10.25(1H, s).

Step 6

The title compound was prepared in a similar manner according to Step 5of the following Production Example 14.

MS (ES+); 334 (M+H)⁺ free

¹H-NMR (DMSO-d₆), δ (ppm): 1.24(3H, t, J=7.0 Hz), 2.80–3.00(4H, m),4.19(2H, q, J=7.0 Hz), 6.76(1H, s), 7.14(2H, d, J=8.4 Hz), 7.28(2H, d,J=8.4 Hz), 7.46(3H, br), 9.91(1H, s).

PRODUCTION EXAMPLE 14 Synthesis ofN-{4-[2-(3-{[amino(imino)methyl]amino}phenyl)ethyl]-5-bromo-1,3-thiazol-2-yl}acetamidehydrochloride

Step 1: N-{4-[2-(3-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (E-Zmixture)

To a solution of 1-(bromomethyl)-3-nitrobenzene (276 mg) inN,N-dimethylformamide (7 mL) was added triphenylphosphine (335 mg) atroom temperature. After the mixed solution was stirred for 4 hours,potassium tert-butoxide (172 mg) andN-(4-formyl-1,3-thiazol-2-yl)acetamide (217 mg) were successively addedto the solution at the same temperature. After the whole solution wasstirred at room temperature for 5 hours, the mixture was poured intowater, the pH of the aqueous layer was adjusted to 7 with1N-hydrochloric acid. The resulting mixture was extracted with ethylacetate. The extract was washed with brine, dried over sodium sulfateand evaporated under reduced pressure. The resulting residue waspurified by column chromatography on silica gel (10 g) using a mixedsolvent of n-hexane and ethyl acetate (4:1). The fractions containingthe objective compound were collected and evaporated under reducedpressure to give brown powder of the title compound (E-Z mixture) (323mg, 87.4%).

¹H-NMR (DMSO-d₆) (cis-trans product mixture), δ (ppm): 2.11(2.49H, s),2.16(0.51H, s), 6.66(1.66H, s), 7.13(0.83H, s), 7.28(0.17H, s), 7.29,7.46(0.34H, ABq, J=16 Hz), 7.60(1H, t, J=7.9 Hz), 7.91(0.83H, d, J=7.9Hz), 8.01(0.17H, d, J=7.9 Hz), 8.09–8.13(1H, m), 8.28(0.83H, m),8.38(0.17H, m).

Step 2: N-{4-[2-(3-aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide

N-{4-[2-(3-Nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (E,Z mixture)(315 mg) in a mixed solvent of methyl alcohol (3 ml), tetrahydrofuran (6ml), and acetic acid (1 ml) was hydrogenated over 10% Palladium oncarbon (50% wet, 200 mg) under 4.3 atmospheric pressure at roomtemperature for 3 hours. The catalyst was removed off by filtration, andthe filtrate was evaporated in vacuo. The residue was poured into water,the pH of the aqueous layer was adjusted to 9 with aqueous sodiumhydrogen carbonate. The resulting mixture was extracted with ethylacetate. The extract was washed with brine, dried over magnesium sulfateand evaporated under reduced pressure. The resulting residue waspurified by column chromatography on silica gel (9 g) using a mixedsolvent of n-hexane and ethyl acetate (2:1 to 1:1). The fractionscontaining the objective compound were collected and evaporated underreduced pressure to give syrup. The syrup of the objective compound waschanged to solid in freezer (275 mg, 96.6%).

MS (ES+); 262 (M+H)⁺

¹H-NMR (CDCl₃), δ (ppm): 2.23(3H, s), 2.80–3.00(4H, m), 3.60(2H, br),6.51(1H, s), 6.45–6.65(3H, m), 7.06(1H, t, J=7.9 Hz), 9.45(1H, br).

Step 3:N-{4-[2-(3-{[N′,N″-bis(tert-butoxycarbonyl)amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide

To a solution ofN-{4-[2-(3-aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (267 mg) intetrahydrofuran (3 ml) was addedN,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (317 mg) atroom temperature. After the mixed solution was stirred for 3 days at thesame temperature, and then evaporated under reduced pressure, theresulting residue was purified by column chromatography on silica gel(10 g) using a mixed solvent of n-hexane and ethyl acetate (4:1 to 3:2).The fractions containing the objective compound were collected andevaporated under reduced pressure to give colorless foam of the titlecompound (316 mg, 61.4%).

MS (ES+); 504 (M+H)⁺

¹H-NMR (CDCl₃), δ (ppm): 1.40–1.80(18H, m), 2.25(3H, s), 2.97(4H, m),6.37(1H, m), 6.53(1H, s), 6.91(1H, d, J=7.9 Hz), 7.23(1H, t, J=7.9 Hz),7.34(1H, s), 7.52(1H, d, J=7.9 Hz), 7.63–7.64(1H, m), 10.28(1H, s).

Step 4:N-{4-[2-(3-{[N′,N″-bis(tert-butoxycarbonyl)amino(imino)methyl]amino}phenyl)ethyl]-5-bromo-1,3-thiazol-2-yl}acetamide

To a suspension ofN-{4-[2-(3-{[N′,N″-bis(tert-butoxycarbonyl)amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide(115 mg) in methanol (3 ml) was added N-bromosuccinimide (44.7 mg) atroom temperature. After the mixed solution was stirred at the sametemperature for 1 hour, the resulting precipitate was collected byfiltration, washed with a mixed solvent of diisopropyl ether andn-hexane (1:1). The title compound was obtained as white powder (70 mg,52.6%).

MS (ES+); 582 (M+H)⁺

¹H-NMR (CDCl₃), δ (ppm): 1.40–1.75(18H, m), 2.21(3H, s), 2.85–3.00(4H,m), 6.93(1H, d, J=7.9 Hz), 7.23(1H, t, J=7.9 Hz), 7.30(1H, s), 7.51(1H,d, J=7.9 Hz), 9.26(1H, br), 10.26(1H, br), 11.63(1H, br).

Step 5

To a solution ofN-{4-[2-(3-{[N′,N″-bis(tert-butoxycarbonyl)amino(imino)methyl]amino}phenyl)ethyl]-5-bromo-1,3-thiazol-2-yl}acetamide(64 mg) in dichloromethane (0.5 ml) was added dropwise 4N-hydrogenchloride in 1,4-dioxane (2 ml) at room temperature. After being stirredat the same temperature for 20 hours, the reaction mixture wasconcentrated under reduced pressure. The resulting residue was dissolvedin a minimum methanol, and the solution was gradually diluted with ethylacetate. The resulting precipitate was collected by filtration, washedwith diisopropyl ether. The title compound was obtained as colorlesspowder (37 mg, 80.4%).

MS (ES+); 382 (M+H)⁺ free

¹H-NMR (DMSO-d₆), δ (ppm): 2.14(3H, s), 2.80–3.00(4H, m), 7.00–7.15(3H,m), 7.35(1H, t, J=7.9 Hz), 7.51(4H, br), 10.01(1H, br), 12.42(1H, br).

PRODUCTION EXAMPLE 15 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-bromo-1,3-thiazol-2-yl}acetamidehydrochloride

Step 1-a

Di-tert-butyl{[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound of Step 6 of Production Example 1 in asimilar manner according to the following Step 5 of Production Example18.

mp. 275.5–276° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.11(3H, s),2.82–2.96(4H, m), 6.74(1H, s), 7.18(2H, d, J=8.5 Hz), 7.42(2H, d, J=8.5Hz), 9.94(1H, brs), 11.44(1H, brs), 12.09(1H, brs).

MS: 504(M+H)⁺

Step 1-b

Di-tert-butyl{[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate(310 mg) prepared in a similar manner according to Step 5 of thefollowing Production Example 18 was dissolved in methanol (6 ml) andtetrahydrofuran (3 ml) under nitrogen atmosphere. ThenN-bromosuccinimide (164 mg) was added to the solution at 0° C. Thereaction mixture was stirred at room temperature for 4 hours, andconcentrated in vacuo. Chloroform and saturated sodium hydrogencarbonate solution were added to the residue. The organic layer waswashed with water and saturated sodium chloride solution, dried overanhydrous magnesium sulfate, and concentrated in vacuo. The residue waspurified by flash column chromatography over silica gel withn-hexane/ethyl acetate (2:1) as an eluent to give di-tert-butyl{[(4-{2-[2-(acetylamino)-5-bromo-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate(271.4 mg) as a colorless amorphous substance.

¹H-NMR (CDCl₃), δ (ppm): 1.49(9H, s), 1.53(9H, s), 2.22(3H, s), 2.90(4H,s), 7.13(2H, d, J=8.0 Hz), 7.45(2H, d, J=8.0 Hz).

MS: 582(M+H)⁺

Step 2

Di-tert-butyl{[(4-{2-[2-(acetylamino)-5-bromo-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate(113 mg) and 4N hydrochloric acid in 1,4-dioxane solution (2 ml) werecombined under nitrogen atmosphere. The reaction mixture was stirred atroom temperature for 24 hours. The solvent was removed in vacuo. Theresidue was washed with ethyl acetate to giveN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-bromo-1,3-thiazol-2-yl}acetamidehydrochloride (16.8 mg) as a pale yellow amorphous solid.

¹H-NMR (DMSO-d₆), δ (ppm): 2.14(3H, s), 2.82–2.97(4H, m), 7.14(2H, d,J=8.5 Hz), 7.25(2H, d, J=8.5 Hz), 7.40(3H, brs), 9.81(1H, brs),12.41(1H, brs).

MS: 382(M+H)⁺ free

PRODUCTION EXAMPLE 16 Synthesis ofN-[4-(2-{4-[(aminooxy)methyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide

Step 1

[4-(Methoxycarbonyl)benzyl](triphenyl)phosphonium bromide (6.06 g) andN,N-dimethylformamide (50 ml) were combined under nitrogen atmosphere.Then potassium tert-butoxide (1.66 g) andN-(4-formyl-1,3-thiazol-2-yl)acetamide (2.1 g) prepared in a similarmanner according to Step 4 of Production Example 1 were added to thesuspension at 0° C. The reaction mixture was stirred at room temperaturefor 6 hours, poured into ice-water, and extracted with ethyl acetate.The organic layer was washed with 1N-hydrochloric acid, water andsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated in vacuo. The residue was purified by flashcolumn chromatography over silica gel with chloroform/methanol(20:1→10:1) as an eluent, and triturated with ethyl ether to give amixture of methyl4-{(Z)-2-[2-(acetylamino)-1,3-thiazol-4-yl]ethenyl}benzoate and methyl4-{(E)-2-[2-(acetylamino)-1,3-thiazol-4-yl]ethenyl}benzoate (Z:E=3:1)(4.05 g) as a colorless solid.

mp. 164–165.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.13(3H×¾, s), 2.16(3H×¼, s), 3.85(3H, s),6.61(2H×¾, s), 7.05(1H×¾, s), 7.26(1H×¼, d, J=15.5 Hz), 7.27(1H×¼, s),7.37(1H×¼, d, J=15.5 Hz), 7.64(2H×¾, d, J=8.5 Hz), 7.69(2H×¼, d, J=8.5Hz), 7.90(2H×¾, d, J=8.5 Hz), 7.94(2H×¼, d, J=8.5 Hz), 12.05(1H, brs).

MS: 303(M+H)⁺

Step 2

Methyl 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzoate wasprepared in a similar manner according to Step 2 of Production Example9.

mp. 170–171° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.86–2.95(2H, m), 2.97–3.05(2H,m), 3.83(3H, s), 6.72(1H, s), 7.35(2H, d, J=8.5 Hz), 7.87(2H, d, J=8.5Hz), 12.08(1H, brs).

MS: 305 (M+H)⁺

Step 3

To a stirred solution of methyl4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzoate (1.8 g) in drytetrahydrofuran (36 ml) was added dropwise 1.0 M diisobutylaluminiumhydride solution in toluene (20.7 ml) at −78° C. over 15 minutes undernitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 1.5 hours, and then the reaction was quenched with water(1 ml). The mixture was stirred at room temperature for 30 minutes,dried over anhydrous magnesium sulfate, and filtered through a pad ofCelite. The solvent was evaporated in vacuo. The residual solid waswashed with ethyl ether to giveN-(4-{2-[4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (1.03g) as a colorless solid.

mp. 162–165° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.80–2.95(4H, m), 4.44(2H, d,J=5.5 Hz), 5.09(1H, t, J=5.5 Hz), 6.72(1H, s), 7.14(2H, d, J=8.0 Hz),7.21(2H, d, J=8.0 Hz), 12.08(1H, brs).

MS: 277(M+H)⁺

Step 4

N-(4-{2-[4-(Hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (250mg), 2-hydroxy-1H-isoindole-1,3(2H)-dione (155 mg), triphenylphosphine(249 mg) and tetrahydrofuran (5 ml) were combined under nitrogenatmosphere, and then diethyl azodicarboxylate (0.15 ml) was added to thesolution at 0° C. The reaction mixture was stirred at room temperaturefor 6 hours, poured into saturated sodium hydrogen carbonate solution,and extracted with ethyl acetate. The organic layer was washed withsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated in vacuo. The residue was purified by flashcolumn chromatography over silica gel with chloroform/methanol (20:1) asan eluent, and triturated with ethyl acetate to giveN-{4-[2-(4-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide(218.2 mg) as a colorless solid.

mp. 225–226° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.82–3.00(4H, m), 5.12(2H, s),6.69(1H, s), 7.23(2H, d, J=8.0 Hz), 7.41(2H, d, J=8.0 Hz), 7.86(4H, s),12.08(1H, brs).

MS: 422(M+H)⁺

Step 5

N-{4-[2-(4-{[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide(200 mg), methylhydrazine (0.038 ml) and dichloromethane (4 ml) werecombined under nitrogen atmosphere. The reaction mixture was stirred atroom temperature for 1.5 hours, and filtered in vacuo. The filtrate waswashed with saturated sodium hydrogen carbonate solution, water andsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated in vacuo. The residual solid was washed withacetonitrile to giveN-[4-(2-{4-[(aminooxy)methyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide(81.8 mg) as a colorless solid.

mp. 130–130.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.82–2.97(4H, m), 4.51(2H, s),6.01(2H, s), 6.73(1H, s), 7.17(2H, d, J=8.0 Hz), 7.22(2H, d, J=8.0 Hz),12.09(1H, brs).

MS: 292(M+H)⁺

PRODUCTION EXAMPLE 17 Synthesis ofN-{4-[2-(4-{[(methyleneamino)oxy]methyl}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide

N-[4-(2-{4-[(Aminooxy)methyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide(30 mg) prepared in a similar manner according to Production Example 16,37% formaldehyde (8 μl) and dry methanol (1 ml) were combined undernitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 6 hours and concentrated in vacuo. The residue waspurified by preparative silica gel column chromatography withchloroform/methanol (20:1) as an eluent, and triturated with ethyl etherto giveN-{4-[2-(4-{[(methyleneamino)oxy]methyl}-phenyl)ethyl]-1,3-thiazol-2-yl}acetamide(20.9 mg) as a colorless solid.

mp. 136.5–137° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.83–2.97(4H, m), 5.01(2H, s),6.61(1H, d, J=7.5 Hz), 6.73(1H, s), 7.09(1H, d, J=7.5 Hz), 7.18(2H, d,J=8.0 Hz), 7.24(2H, d, J=8.0 Hz), 12.08(1H, brs).

MS: 304(M+H)⁺

PRODUCTION EXAMPLE 18 Synthesis ofN-{5-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamidehydrochloride

Step 1

A solution of 1,1,3,3-tetramethoxypropane (10 g) and hydrochloric acidconcentrate (0.43 ml) in water (11 ml) was stirred at room temperaturefor 10 minutes. Bromine (3.14 ml) was added dropwise to the solution atroom temperature over 50 minutes. The reaction mixture was stirred atroom temperature for 20 minutes, and concentrated in vacuo. The residualsolid was washed with water to give 2-bromomalonaldehyde (3.6 g) as ayellow solid.

mp. 147–148° C.

¹H-NMR (CDCl₃), δ (ppm): 4.73–4.80(1H, m), 8.47(2H, brs).

MS: 149(M−H)⁺

Step 2

N′-((E)-Ethanoyl)carbamimidothioic acid (2.74 g) and acetone (20 ml)were combined under nitrogen atmosphere. Then 2-bromomalonaldehyde (3.5g) was added to the solution under reflux. The reaction mixture wasrefluxed for an hour, and cooled to room temperature. The precipitatewas filtered in vacuo. The solid was washed with water and acetone, andpurified by flash column chromatography over silica gel withchloroform/methanol (20:1) as an eluent to giveN-(5-formyl-1,3-thiazol-2-yl)acetamide (1.21 g) as an off-white solid.

mp. 235–235.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.21(3H, s), 8.41(1H, s), 9.95(1H, s),12.71(1H, brs).

MS: 169(M−H)⁺

Step 3

N-{5-[(Z)-2-(4-Nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide wasprepared in a similar manner according to Step 5 of Production Example1.

mp. 221–223° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.07(3H, s), 6.63(1H, d, J=12.0 Hz), 6.92(1H,d, J=12.0 Hz), 7.55(1H, s), 7.62(2H, d, J=9.0 Hz), 8.24(2H, d, J=9.0Hz), 12.16(1H, brs).

MS: 290(M+H)⁺

Step 4

A mixture ofN-{5-[(Z)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (1 g) and10% palladium carbon (1.04 g) in ethyl acetate (100 ml) andN,N-dimethylformamide (20 ml) was stirred under 4 atm hydrogen atambient temperature for 4 hours. The reaction mixture was filteredthrough a celite pad, and the filtrate was concentrated in vacuo. Theresidue was purified by flash column chromatography over silica gel withchloroform/methanol (30:1→20:1) as an eluent, and triturated with ethylether to give N-{5-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide(240.9 mg) as an off-white solid.

mp. 218–219.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.70(2H, t, J=7.5 Hz), 2.92(2H,t, J=7.5 Hz), 4.85(2H, s), 6.47(2H, d, J=8.5 Hz), 6.86(2H, d, J=8.5 Hz),7.08(1H, s), 11.86(1H, brs).

MS: 262(M+H)⁺

Step 5

N-{5-[2-(4-Aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (100 mg),N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (119 mg),N,N-dimethylformamide (1 ml) and tetrahydrofuran (2 ml) were combinedunder nitrogen atmosphere. The reaction mixture was stirred at 50° C.for 5.5 hours. After cooled to room temperature, the reaction mixturewas concentrated in vacuo. The residue was purified by preparativesilica gel column chromatography with n-hexane/ethyl acetate (1:2) as aneluent to give di-tert-butyl{[(4-{2-[2-(acetylamino)-1,3-thiazol-5-yl]ethyl}phenyl)amino]methylidene}biscarbamate(93.9 mg) as a colorless solid.

mp. 203–205° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.40(9H, s), 1.51(9H, s), 2.10(3H, s),2.87(2H, t, J=7.5 Hz), 3.02(2H, t, J=7.5 Hz), 7.11(1H, s), 7.21(2H, d,J=8.5 Hz), 7.45(2H, d, J=8.5 Hz), 9.96(1H, brs), 11.43(1H, brs),11.88(1H, brs).

MS: 504(M+H)⁺

Step 6

The title compound was prepared in a similar manner according to Step 2of Production Example 15.

mp. 105–107° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.91(2H, t, J=7.5 Hz), 3.04(2H,t, J=7.5 Hz), 7.14(1H, s), 7.14(2H, d, J=8.5 Hz), 7.32(2H, d, J=8.5 Hz),7.46(3H, brs), 9.89(1H, s), 11.95(1H, brs).

MS: 304(M+H)⁺ free

PRODUCTION EXAMPLE 19 Synthesis ofN-{4-[2-(4-{[imino(methylamino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide

A mixture of methylN-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)imidothiocarbamatehydriodide (50 mg) prepared in a similar manner according to ProductionExample 4, 40% methylamine in methanol (0.056 ml) and ethanol (1 ml) wasstirred at ambient temperature for 20 hours. The precipitated crystalswere filtered and washed with ethanol to giveN-{4-[2-(4-{[imino(methylamino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide(18 mg).

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.64(3H, s), 2.83(4H, s),6.67(2H, d, J=7 Hz), 6.73(1H, s), 7.01(2H, d, J=7 Hz).

MS (M+H)=318

PRODUCTION EXAMPLE 20 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-chloro-1,3-thiazol-2-yl}acetamidehydrochloride

Step 1

Di-tert-butyl{[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate(150 mg) prepared in a similar manner according to Step 5 of ProductionExample 18 was dissolved in methanol (1.5 ml) and tetrahydrofuran (3 ml)under nitrogen atmosphere. Then N-chlorosuccinimide (59.7 mg) was addedto the solution at 0° C. The reaction mixture was stirred at roomtemperature for 29 hours, and diluted in ethyl acetate. The organicsolution was washed with saturated sodium hydrogen carbonate solution,water and saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated in vacuo. The residual solid waswashed with ethyl ether to give di-tert-butyl{[(4-{2-[2-(acetylamino)-5-chloro-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate(111 mg) as an off-white solid.

mp. 220–221° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.13(3H, s),2.81–2.94(4H, m), 7.15(2H, d, J=8.5 Hz), 7.43(2H, d, J=8.5 Hz), 9.95(1H,brs), 11.43(1H, brs), 12.38(1H, brs).

MS: 538(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 2of Production Example 15.

mp. 82–84° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.14(3H, s), 2.82–2.97(4H, m), 7.14(2H, d,J=8.5 Hz), 7.25(2H, d, J=8.5 Hz), 7.42(3H, brs), 9.85(1H, brs),12.38(1H, brs).

MS: 338(M+H)⁺ free

PRODUCTION EXAMPLE 21 Synthesis ofN-(4-{2-[4-({[amino(imino)methyl]amino}methyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamidehydrochloride

Step 1

A mixture ofN-(4-{2-[4-(aminomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (20 mg)prepared in a similar manner according to Production Example 12,N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (23 mg) andtetrahydrofuran (0.5 ml) was stirred at ambient temperature for 1 hour.The reaction mixture was concentrated in vacuo, and the residue waspurified by flash column chromatography on silica-gel with chloroform asan eluent. The crystalline residue was collected and washed withdiisopropyl ether to givedi-tert-butyl{[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzyl)amino]methylidene}biscarbamate(22 mg).

¹H-NMR (CDCl₃), δ (ppm): 1.47(9H, s), 1.50(9H, s), 2.24(3H, s),2.87–3.03(4H, m), 6.50(1H, s), 7.13(2H, d, J=7 Hz), 7.22(2H, d, J=7 Hz).

MS (M+H)=518

Step 2

A mixture ofdi-tert-butyl{[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzyl)amino]methylidene}biscarbamate(20 mg), dichloromethane (2 drops) and 4N hydrogen chloride in1,4-dioxane (0.5 ml) was stirred for 15 hours. The precipitated crystalswere filtered and washed with 1,4-dioxane to giveN-(4-{2-[4-({[amino(imino)methyl]amino}methyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamidehydrochloride (13 mg).

¹H-NMR (DMSO-d₆), δ (ppm): 2.12(3H, s), 2.80–3.00(4H, m), 4.32(2H, d,J=7 Hz), 6.73(1H, s), 7.20(4H, s), 8.04(1H, t, J=7 Hz).

MS (M+H)=318

PRODUCTION EXAMPLE 22 Synthesis of ethyl2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazole-5-carboxylatehydrochloride

Step 1

Ethyl 4-chloro-3-oxobutanoate (35 g) was dissolved in dichloromethane(70 ml), and then sulfuryl chloride (17.1 ml) in dichloromethane (20 ml)was added dropwise to the solution at 0° C. over 15 minutes undernitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 3 hours, and concentrated in vacuo. The residual oil,N′-((E)-ethanoyl)carbamimidothioic acid (25.1 g) and acetone (600 ml)were combined. The reaction mixture was refluxed for 2.5 hours. Aftercooled to room temperature, the mixture was concentrated in vacuo. Theresidual solid was washed with water and isopropyl ether to give ethyl2-(acetylamino)-4-(chloromethyl)-1,3-thiazole-5-carboxylate (21.2 g) asa pale yellow solid.

mp. 164–165° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.30(3H, t, J=7.0 Hz), 2.19(3H, s), 4.29(2H,q, J=7.0 Hz), 5.00(2H, s), 12.72(1H, s).

MS: 263(M+H)⁺

Step 2: ethyl2-(acetylamino)-4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazole-5-carboxylate

To a stirring solution of ethyl2-(acetylamino)-4-(chloromethyl)-1,3-thiazole-5-carboxylate (1.0 g, 3.81mmol) in N,N-dimethylformamide (20 mL) was added triphenylphosphine (1.2g, 4.57 mmol) at room temperature. The resultant mixture was stirred at65° C. for 5 hours. To the mixture was added potassium tert-butoxide(555 mg, 4.95 mmol) at 5° C., and the resultant mixture was stirred at5° C. for 30 minutes. p-Nitrobenzaldehyde (805 mg, 5.33 mmol) was addedat 5° C.

After stirring for 1 hour at room temperature, the reaction was quenchedwith water, and the mixture was filtered to give the title compound (1.0g, 72.7%) as a yellow solid.

¹H-NMR (CDCl₃), δ (ppm): 1.40(3H, t, J=7.2 Hz), 2.33(3H, s), 4.38(2H, q,J=7.2 Hz), 7.59(1H, d, J=16.0 Hz), 7.70(2H, d, J=8.8 Hz), 8.18(1H, d,J=16.0 Hz), 8.22(2H, d, J=8.8 Hz), 8.90(1H, m).

Step 3

Ethyl2-(acetylamino)-4-[2-(4-aminophenyl)ethyl]-1,3-thiazole-5-carboxylatewas prepared in a similar manner according to Step 6 of ProductionExample 1.

¹H-NMR (CDCl₃), δ (ppm): 1.35(3H, t, J=7.0 Hz), 2.27(3H, s), 2.84(2H,m), 3.28(2H, m), 3.56(2H, m), 4.31(2H, q, J=7.0 Hz), 6.61(2H, d, J=8.3Hz), 7.01(2H, d, J=8.3 Hz), 9.12(1H, m).

Step 4

Ethyl2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazole-5-carboxylatewas prepared in a similar manner according to Step 5 of ProductionExample 18.

¹H-NMR (CDCl₃), δ (ppm): 1.36(3H, t, J=7.4 Hz), 1.49(9H, s), 1.53(9H,s), 2.25(3H, s), 2.94(2H, m), 3.34(2H, m), 4.31(2H, q, J=7.4 Hz),7.15(2H, d, J=8.4 Hz), 7.41(2H, d, J=8.4 Hz), 9.69(1H, m), 10.20(1H, s),11.63(1H, s).

Step 5

The title compound was prepared in a similar manner according to Step 2of Production Example 15.

¹H-NMR (DMSO-d₆), δ (ppm): 1.28(3H, t, J=7.0 Hz), 2.18(3H, s), 2.94(2H,m), 3.28(2H, m), 4.23(2H, q, J=7.0 Hz), 7.16(2H, d, J=8.4 Hz), 7.29(2H,d, J=8.4 Hz), 7.37(3H, s), 9.71(1H, s), 12.55(1H, s).

PRODUCTION EXAMPLE 23 Synthesis ofN-{4-[2-(4-{[(ethylamino)(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared in a similar manner according toProduction Example 19.

¹H-NMR (DMSO-d₆), δ (ppm): 1.13(3H, t, J=6 Hz), 2.11(3H, s),2.70–3.00(6H, m), 6.70(1H, s), 6.77(2H, d, J=7 Hz), 7.17(2H, d, J=7 Hz).

MS (M+H)=332

PRODUCTION EXAMPLE 24 Synthesis of benzyl4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-carbamate

Step 1

To an ice-cold mixture of ethyl 2-amino-1,3-thiazole-4-carboxylate (5g), pyridine (3.36 ml) and dichloromethane (50 ml) was addedbenzyloxycarbonyl chloride (3.1 ml), and the mixture was stirred atambient temperature for 1 hour. The reaction mixture was washed withsaturated aqueous sodium hydrogen bicarbonate (30 ml), dried over sodiumsulfate and concentrated in vacuo. The crystalline residue was collectedand washed with diisopropyl ether to give ethyl2-{[(benzyloxy)carbonyl]amino}-1,3-thiazole-4-carboxylate (5.1 g).

¹H-NMR (CDCl₃), δ (ppm): 1.48(3H, t, J=7 Hz), 4.38(2H, q, J=7 Hz),5.27(2H, s), 7.36–7.44(5H, m), 7.82(1H, s).

MS (M+H)=307

Step 2

Benzyl 4-(hydroxymethyl)-1,3-thiazol-2-ylcarbamate was prepared in asimilar manner according to Step 2 of Production Example 6.

¹H-NMR (CDCl₃), δ (ppm): 4.56(2H, s), 5.27(2H, s), 6.80(1H, s),7.30–7.46(5H, m).

MS (M+H)=265

Step 3

Benzyl 4-formyl-1,3-thiazol-2-ylcarbamate was prepared in a similarmanner according to Step 3 of Production Example 6.

¹H-NMR (CDCl₃), δ (ppm): 5.29(2H, s), 7.35–7.45(5H, m), 7.81(1H, s),9.80(1H, s).

MS (M+H)=263

Step 4

Benzyl 4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-ylcarbamate wasprepared in a similar manner according to Step 4 of Production Example6.

¹H-NMR (DMSO-d₆), δ (ppm): 5.23(2×⅗H, s), 5.25(2×⅖H, s), 6.56–6.70(1H,m), 7.23(1H, s), 7.30–7.50(5H, m), 7.82(2×⅖H, d, J=7 Hz), 7.92(2×⅗H, d,J=7 Hz), 8.14(2×⅗H, d, J=7 Hz), 8.21(2×⅖H, d, J=7 Hz).

MS (M+H)=382

Step 5

A mixture of benzyl4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-ylcarbamate (1.4 g),palladium on carbon (140 mg) and methanol (2 ml) was stirred underhydrogen atmosphere (4 atm) at ambient temperature for 8 hours. Thecatalyst was filtered off, and the filtrate was concentrated in vacuo togive benzyl 4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-ylcarbamate (1.2g).

¹H-NMR (CDCl₃), δ (ppm): 2.77–2.90(4H, m), 5.22(2H, s), 6.43(1H, s),6.60(2H, d, J=7 Hz), 6.92(2H, d, J=7 Hz), 7.32–7.40(5H, m).

MS (M+H)=354

Step 6

A mixture of benzyl 4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-ylcarbamate(25 mg), cyanamide (6.0 mg), 4N hydrogen chloride in ethyl acetate(0.018 ml) and ethanol (1 ml) was stirred at 100° C. for 72 hours. Thereaction mixture was concentrated in vacuo. To the residue was addedethyl acetate (5 ml) and saturated aqueous sodium hydrogen bicarbonate(5 ml). The precipitated solid was filtered and washed with ethylacetateand water to give benzyl4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-carbamate(15 mg).

¹H-NMR (DMSO-d₆), δ (ppm): 2.63–2.75(4H, m), 5.07(2H, s), 6.40(1H, s),6.94(2H, d, J=7 Hz), 7.25–7.40(7H, m).

MS (M+H)=396

PRODUCTION EXAMPLE 25 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}benzamidehydrochloride

Step 1

Benzyl 4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-ylcarbamate (2.7g) prepared in a similar manner according to Step 4 of ProductionExample 24 and 6N hydrochloric acid (50 ml) were combined. The reactionmixture was refluxed for 3 hours. After cooled to room temperature, theprecipitate was filtered in vacuo. The solid was washed with water andacetonitrile to give4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-amine (1.34 g) as ayellow solid.

mp. 278–278.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 7.02(1H, s), 7.33(2H, s), 7.77(2H, d, J=8.5Hz), 8.25(2H, d, J=8.5 Hz).

MS: 248(M+H)⁺

Step 2

4-[(E)-2-(4-Nitrophenyl)ethenyl]-1,3-thiazol-2-amine (300 mg) andN,N-dimethylaniline (4 ml) were combined under nitrogen atmosphere, andthen benzoyl chloride (0.31 ml) was added dropwise to the suspension.The reaction mixture was stirred at 110° C. for 2 hours. After cooled toroom temperature, the mixture was diluted with ethyl acetate. Theorganic solution was washed with 1N hydrochloric acid, water, saturatedsodium hydrogen carbonate solution and saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and concentrated invacuo. The residual solid was washed with ethyl ether to giveN-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}benzamide (298.6mg) as a yellow solid.

mp. 224.5–225° C.

¹H-NMR (DMSO-d₆), δ (ppm): 7.40(1H, d, J=16.0 Hz), 7.45(1H, s), 7.53(1H,d, J=16.0 Hz), 7.56(2H, t, J=7.0 Hz), 7.66(1H, t, J=7.0 Hz), 7.84(2H, d,J=8.5 Hz), 8.13(2H, d, J=7.0 Hz), 8.23(2H, d, J=8.5 Hz), 12.80(1H, brs).

MS: 352(M+H)⁺

Step 3

N-{4-[2-(4-Aminophenyl)ethyl]-1,3-thiazol-2-yl}benzamide was prepared ina similar manner according to Step 2 of Production Example 9.

¹H-NMR (CDCl₃), δ (ppm): 2.82(4H, s), 3.57(2H, brs), 6.53(1H, s),6.61(2H, d, J=8.0 Hz), 6.92(2H, d, J=8.0 Hz), 7.50(2H, t, J=7.0 Hz),7.60(1H, t, J=7.0 Hz), 7.93(2H, d, J=7.0 Hz), 10.15(1H, brs).

MS: 324(M+H)⁺

Step 4

Di-tert-butyl{[(4-{2-[2-(benzoylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in a similar manner according to Step 5 of ProductionExample 18.

mp. 143–144° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.95(4H, s),6.86(1H, s), 7.22(2H, d, J=8.5 Hz), 7.44(2H, d, J=8.5 Hz), 7.54(2H, t,J=7.5 Hz), 7.63(1H, t, J=7.5 Hz), 8.10(2H, d, J=7.5 Hz), 9.94(1H, s),11.44(1H, brs), 12.66(1H, brs).

MS: 566(M+H)⁺

Step 5

The title compound was prepared in a similar manner according to Step 2of Production Example 15.

mp. 229–232° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.91–3.05(4H, m), 6.88(1H, s), 7.15(2H, d,J=8.5 Hz), 7.32(2H, d, J=8.5 Hz), 7.44(3H, brs), 7.54(2H, t, J=7.5 Hz),7.64(1H, t, J=7.5 Hz), 8.10(2H, d, J=7.5 Hz), 9.88(1H, s).

MS: 366(M+H)⁺ free

PRODUCTION EXAMPLE 26 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamidehydrochloride

Step 1

4-(Methylsulfanyl)benzaldehyde (31.8 g), (acetylamino)acetic acid (24.5g) and acetic anhydride (35 ml) were combined, and then sodium acetate(8.57 g) was added to the suspension at room temperature under nitrogenatmosphere. The reaction mixture was refluxed for 3.5 hours. Aftercooled to room temperature, the mixture was poured into ice-water andethyl acetate with stirring, and filtered in vacuo. The filtrate wasseparated. The organic layer was washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and concentrated invacuo. The residue and the previously obtained solid were combined, andthe mixture was purified by flash column chromatography over silica gelwith chloroform/ethyl acetate (30:1) as an eluent, and triturated withisopropyl ether to give(4Z)-2-methyl-4-(4-(methylsulfanyl)benzylidene)-1,3-oxazol-5(4H)-one(17.8 g) as a brown solid.

mp. 154–155° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.38(3H, s), 2.53(3H, s), 7.19(1H, s),7.36(2H, d, J=8.5 Hz), 8.12(2H, d, J=8.5 Hz).

Step 2

(4Z)-2-Methyl-4-(4-(methylsulfanyl)benzylidene)-1,3-oxazol-5(4H)-one(17.5 g), 1,4-dioxane (100 ml) and 4N-hydrochloric acid (27 ml) werecombined. The reaction mixture was refluxed for 3 hours. After cooled toroom temperature, the mixture was concentrated in vacuo. Ethyl acetateand water were added to the residue, and the precipitate was filtered invacuo to give 3-(4-(methylsulfanyl)phenyl)-2-oxopropanoic acid (6.7 g)as a pale brown solid.

mp. 165–167° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.48(3H, s), 6.37(1H, s), 7.23(2H, d, J=8.5Hz), 7.70(2H, d, J=8.5 Hz), 9.44(1H, s).

MS: 209(M−H)⁺

Step 3

3-(4-(Methylsulfanyl)phenyl)-2-oxopropanoic acid (16.2 g),N,N-dimethylformamide (81 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene(11.5 ml) were combined at 0° C. under nitrogen atmosphere. The mixturewas stirred at the same temperature for an hour, and then iodomethane(9.59 ml) was added to the solution at the same temperature. Thereaction mixture was stirred at room temperature for 4 hours, pouredinto 1N-hydrochloric acid, and extracted with ethyl acetate (twice). Thecombined organic layer was washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and concentrated invacuo. The residue was purified by flash column chromatography oversilica gel with chloroform/ethyl acetate (30:1) as an eluent, andtriturated with isopropyl ether/n-hexane to give methyl3-(4-(methylsulfanyl)phenyl)-2-oxopropanoate (8.6 g) as a dark yellowsolid.

mp. 112–113° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.48(3H, s), 3.79(3H, s), 6.41(1H, s),7.24(2H, d, J=8.5 Hz), 7.72(2H, d, J=8.5 Hz), 9.52(1H, brs).

MS: 223(M−H)⁺

Step 4

Methyl 3-(4-(methylsulfanyl)phenyl)-2-oxopropanoate (2.84 g), pyridiniumtribromide (4.95 g), dichloromethane (140 ml) and acetic acid (0.5 ml)were combined at 0° C. under nitrogen atmosphere. The reaction mixturewas stirred at 0° C. for 2 hours, and poured into water. The mixture wasextracted with ethyl acetate (twice). The combined organic layer wasdried over anhydrous magnesium sulfate, and concentrated in vacuo. Theresidual oil was dissolved in ethanol (55 ml), and then thiourea (1.25g) was added to the solution. The reaction mixture was refluxed for 1hour under nitrogen atmosphere. After cooled to 0° C., water was addedto the solution. The precipitate was filtered in vacuo to give methyl2-amino-5-[4-(methylthio)phenyl]-1,3-thiazole-4-carboxylate (2.67 g) asa brown solid.

mp. 184–185° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.50(3H, s), 3.64(3H, s), 7.25(2H, d, J=8.5Hz), 7.34(2H, d, J=8.5 Hz).

MS: 281(M+H)⁺

Step 5

Methyl 2-amino-5-[4-(methylthio)phenyl]-1,3-thiazole-4-carboxylate (8.8g) was dissolved in pyridine (88 ml), and then acetyl chloride (6.7 ml)was added dropwise to the solution at 0° C. under nitrogen atmosphere.The reaction mixture was stirred at room temperature for 30 minutes andat 50° C. for 2 hours. After cooled to 0° C., water was added to thesolution. The precipitate was filtered in vacuo, and the solid waswashed with ethyl ether to give methyl2-(acetylamino)-5-[4-(methylthio)phenyl]-1,3-thiazole-4-carboxylate (9.3g) as an off-white solid.

mp. 253–254.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 2.52(3H, s), 3.70(3H, s),7.30(2H, d, J=8.5 Hz), 7.44(2H, d, J=8.5 Hz).

MS: 323(M+H)⁺

Step 6

Methyl2-(acetylamino)-5-[4-(methylthio)phenyl]-1,3-thiazole-4-carboxylate (200mg) was dissolved in tetrahydrofuran (2 ml), and then lithium aluminiumhydride (35.3 mg) was added portionwise to the solution at 0° C. Thereaction mixture was stirred at 0° C. for 30 minutes and at roomtemperature for 30 minutes, and quenched with methanol. Ethyl acetateand 1N hydrochloric acid were added to the mixture, and extracted. Theaqueous layer was extracted with ethyl acetate (twice). The combinedorganic layer was washed with saturated sodium chloride solution, driedover anhydrous magnesium sulfate, and concentrated in vacuo. Theresidual solid was dissolved in methanol (0.4 ml) and chloroform (7 ml).Then manganase (IV) oxide (1.08 g) was added to the solution undernitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 13 hours, and filtered through a celite pad. Thefiltrate was concentrated in vacuo. The residue was purified by flashcolumn chromatography over silica gel with chloroform/methanol (20:1) asan eluent to giveN-{4-formyl-5-[4-(methylthio)phenyl]-1,3-thiazol-2-yl}acetamide (153.6mg) as a pale brown amorphous substance.

¹H-NMR (DMSO-d₆), δ (ppm): 2.18(3H, s), 2.54(3H, s), 7.38(2H, d, J=8.5Hz), 7.58(2H, d, J=8.5 Hz), 9.77(1H, s), 12.59(1H, 20 brs).

MS: 293(M+H)⁺

Step 7

N-{5-[4-(Methylthio)phenyl]-4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamidewas prepared in a similar manner according to Step 1 of ProductionExample 9.

mp. 228–230° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.19(3H, s), 2.54(3H, s), 7.32(1H, d, J=16.0Hz), 7.40(2H, d, J=8.5 Hz), 7.46(1H, d, J=16.0 Hz), 7.47(2H, d, J=8.5Hz), 7.79(2H, d, J=9.0 Hz), 8.19(2H, d, J=9.0 Hz), 12.38(1H, brs).

MS: 412(M+H)⁺

Step 8

Potassium peroxymonosulfate (408 mg) was suspended in water (1 ml) andtetrahydrofuran (1 ml), and thenN-{5-[4-(methylthio)phenyl]-4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide(182 mg) in tetrahydrofuran (3 ml) was added dropwise to the suspensionat 0° C. The reaction mixture was stirred at room temperature for 2hours, and then water was added to the suspension. The precipitate wasfiltered in vacuo. The solid was washed with water and ethyl acetate togiveN-{5-[4-(methylsulfonyl)phenyl]-4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide(83 mg) as a yellow solid.

mp. 294–295° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.21(3H, s), 3.30(3H, s), 7.40(1H, d, J=16.0Hz), 7.54(1H, d, J=16.0 Hz), 7.82(2H, d, J=8.5 Hz), 7.84(2H, d, J=8.5Hz), 8.05(2H, d, J=8.5 Hz), 8.20(2H, d, J=8.5 Hz), 12.51(1H, brs).

MS: 442(M−H)⁺

Step 9

N-{4-[2-(4-Aminophenyl)ethyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamidewas prepared in a similar manner according to Step 2 of ProductionExample 9.

mp. 202–204° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.17(3H, s), 2.77–2.88(4H, m), 3.24(3H, s),6.84(2H, brs), 6.45(2H, d, J=8.5 Hz), 6.77(2H, d, J=8.5 Hz), 7.49(2H, d,J=8.5 Hz), 7.91(2H, d, J=8.5 Hz), 12.34(1H, brs).

MS: 416(M+H)⁺

Step 10

Di-tert-butyl{[(4-{2-[2-(acetylamino)-5-(4-(methylsulfonyl)phenyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in similar manner according to Step 5 of Production Example18.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.17(3H, s),2.97(4H, s), 3.24(3H, s), 7.11(2H, d, J=8.5 Hz), 7.38(2H, d, J=8.5 Hz),7.56(2H, d, J=8.5 Hz), 7.92(2H, d, J=8.5 Hz), 9.92(1H, s), 11.43(1H,brs), 12.34(1H, brs).

MS: 658(M+H)⁺

Step 11

The title compound was prepared in a similar manner according to Step 2of Production Example 15.

mp. 145–146.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.18(3H, s), 2.99(4H, brs), 3.25(3H, s),7.11(2H, d, J=8.0 Hz), 7.22(2H, d, J=8.0 Hz), 7.38(3H, brs), 7.57(2H, d,J=8.0 Hz), 7.94(2H, d, J=8.0 Hz), 9.79(1H, s), 12.36(1H, brs).

MS: 458(M+H)⁺ free

PRODUCTION EXAMPLE 27 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-methyl-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Ethyl2-(acetylamino)-4-[2-(4-aminophenyl)ethyl]-1,3-thiazole-5-carboxylate(310 mg) prepared in a similar manner according to Step 3 of ProductionExample 22 was dissolved in tetrahydrofuran (6 ml) under nitrogenatmosphere. Then di(tert-butyl)dicarbonate (223 mg) in tetrahydrofuran(1 ml) was added to the solution at room temperature. The reactionmixture was refluxed for 2 hours. After cooled to room temperature, themixture was concentrated in vacuo. The residual solid was washed withethyl ether to give ethyl2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylate(370.7 mg) as an off-white 30 solid.

mp. 213–214° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.26(3H, t, J=7.0 Hz), 1.46(9H, s), 2.17(3H,s), 2.85(2H, t, J=7.5 Hz), 3.23(2H, t, J=7.5 Hz), 4.22(2H, q, J=7.0 Hz),7.04(2H, d, J=8.5 Hz), 7.33(2H, d, J=8.5 Hz), 9.23(1H, brs), 12.55(1H,brs).

MS: 434(M+H)⁺

Step 2

Ethyl2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylate(3 g), 1N-aqueous sodium hydroxide solution (17.3 ml) and ethanol (30ml) were combined, and the mixture was refluxed for 5 hours. Aftercooled to room temperature, the organic solvent was removed in vacuo.The aqueous solution was acidified (pH=4) with 1N-hydrochloric acid, andextracted with ethyl acetate (twice). The combined organic layer wasdried over anhydrous magnesium sulfate, and concentrated in vacuo. Theresidual solid was dissolved in pyridine (45 ml), and then acetylchloride (1.48 ml) was added dropwise to the solution at 0° C. undernitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 13 hours, and pyridine was removed in vacuo. Water wasadded to the residue, and acidified with 1N-hydrochloric acid. Theprecipitate was collected in vacuo. The solid was washed with water andethyl ether to give2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylicacid (2.23 g) as an off-white solid.

mp. 237–238° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.46(9H, s), 2.16(3H, s), 2.85(2H, m),3.23(2H, m), 7.04(2H, d, J=8.5 Hz), 7.33(2H, d, J=8.5 Hz), 9.24(1H, s),12.46(1H, s).

MS: 404(M−H)⁺

Step 3

A mixture of2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylicacid (80 mg), 30% methylamine in ethanol solution (0.02 ml),1-hydroxybenzotriazole (29.3 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (39.7 mg) indichloromethane (1 ml) and N,N-dimethylformamide (0.5 ml) was stirred atambient temperature for 20 hours. The reaction mixture was poured intosaturated sodium hydrogen carbonate solution, and extracted withchloroform. The organic layer was washed with water and saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, andconcentrated in vacuo to give tert-butyl4-(2-{2-(acetylamino)-5-[(methylamino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenylcarbamate(92.8 mg) as an off-white amorphous substance.

¹H-NMR (DMSO-d₆), δ (ppm): 1.46(9H, s), 2.15(3H, s), 2.69(3H, d, J=4.5Hz), 2.78–2.86(2H, m), 3.12–3.20(2H, m), 7.06(2H, d, J=8.5 Hz), 7.33(2H,d, J=8.5 Hz), 7.91(1H, q, J=4.5 Hz), 9.22(1H, brs), 12.34(1H, brs).

MS: 419(M+H)⁺

Step 4

tert-Butyl4-(2-{2-(acetylamino)-5-[(methylamino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenylcarbamate(95 mg) and trifluoroacetic acid (2 ml) were combined at 0° C. Thereaction mixture was stirred at room temperature for an hour, andconcentrated in vacuo. The residue was dissolved in chloroform. Theorganic solution was washed with 1N sodium hydroxide solution, water andsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated in vacuo. The residue was purified bypreparative silica gel column chromatography with chloroform/methanol(10:1) as an eluent to give2-(acetylamino)-4-[2-(4-aminophenyl)ethyl]-N-methyl-1,3-thiazole-5-carboxamide(49 mg) as an off-white amorphous substance.

¹H-NMR (DMSO-d₆), δ (ppm): 2.15(3H, s), 2.68(3H, d, J=4.5 Hz),2.67–2.75(2H, m), 3.05–3.15(2H, m), 4.83(2H, brs), 6.47(2H, d, J=8.5Hz), 6.84(2H, d, J=8.5 Hz), 7.85(1H, q, J=4.5 Hz), 12.33(1H, brs).

MS: 319(M+H)⁺

Step 5

Di-tert-butyl{[(4-{2-[2-(acetylamino)-5-(methylaminocarbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in a similar manner according to Step 5 of ProductionExample 18.

mp. 245–246° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.40(9H, s), 1.51(9H, s), 2.14(3H, s),2.68(3H, d, J=4.5 Hz), 2.85–2.94(2H, m), 3.14–3.25(2H, m), 7.17(2H, d,J=8.5 Hz), 7.41(2H, d, J=8.5 Hz), 7.88(1H, q, J=4.5 Hz), 9.94(1H, s),11.44(1H, brs), 12.38(1H, brs).

MS: 561(M+H)⁺

Step 6

The title compound was prepared in a similar manner according to Step 2of Production Example 15.

mp. 101–104° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 2.67(3H, d, J=4.5 Hz),2.86–2.96(2H, m), 3.16–3.26(2H, m), 7.14(2H, d, J=8.5 Hz), 7.26(2H, d,J=8.5 Hz), 7.41(3H, brs), 7.99(1H, q, J=4.5 Hz), 9.81(1H, s), 12.36(1H,brs).

MS: 361(M+H)⁺ free

PRODUCTION EXAMPLE 28 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-phenyl-1,3-thiazole-5-carboxamidehydrochloride

Step 1

A mixture of2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylicacid (80.mg), aniline (0.019 ml),benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(113 mg) and N,N-diisopropylethylamine (0.076 ml) inN,N-dimethylformamide (2 ml) was stirred at ambient temperature for 21hours and at 55 ° C. for 3 hours. The reaction mixture was poured into1N hydrochloric acid, and extracted with chloroform. The organic layerwas washed with water, saturated sodium hydrogen carbonate solution andsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated in vacuo. The residual solid was washed withethyl ether to give tert-butyl4-{2-[2-(acetylamino)-5-(anilinocarbonyl)-1,3-thiazol-4-yl]ethyl}phenylcarbamate(57.2 mg) as a colorless solid.

mp. 199–200° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.46(9H, s), 2.18(3H, s), 2.81–2.91(2H, m),3.14–3.24(2H, m), 7.05(2H, d, J=8.5 Hz), 7.08(1H, t, J=8.5 Hz),7.26–7.36(4H, m), 7.64(2H, d, J=8.5 Hz), 9.22(1H, brs), 9.95(1H, brs),12.44(1H, brs).

MS: 481(M+H)⁺

Step 2

2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-N-phenyl-1,3-thiazole-5-carboxamidewas prepared from tert-butyl4-{2-[2-(acetylamino)-5-(anilinocarbonyl)-1,3-thiazol-4-yl]ethyl}phenylcarbamatein a similar manner according to Step 4 of Production Example 27.

mp. 104–105° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.18(3H, s), 2.71–2.81(2H, m), 3.09–3.18(2H,m), 5.07(2H, brs), 6.48(2H, d, J=8.0 Hz), 6.85(2H, d, J=8.0 Hz),7.08(1H, t, J=8.0 Hz), 7.33(2H, t, J=8.0 Hz), 7.65(2H, d, J=8.0 Hz),9.93(1H, brs), 12.44(1H, brs).

MS: 381(M+H)⁺

Step 3

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-(anilinocarbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from2-(acetylamino)-4-[2-(4-aminophenyl)ethyl]-N-phenyl-1,3-thiazole-5-carboxamidein a similar manner according to Step 5 of Production Example 18.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.18(3H, s),2.87–2.98(2H, m), 3.17–3.29(2H, m), 7.08(1H, t, J=8.0 Hz), 7.16(2H, d,J=8.5 Hz), 7.31(2H, t, J=8.0 Hz), 7.41(2H, d, J=8.5 Hz), 7.64(2H, d,J=8.0 Hz), 9.93(2H, s), 11.43(1H, brs), 12.46(1H, brs).

MS: 623(M+H)⁺

Step 4

The title compound was prepared from di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-(anilinocarbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatein a similar manner according to Step 6 of Production Example 27.

mp. 152–155° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.19(3H, s), 2.90–3.01(2H, m), 3.17–3.29(2H,m), 7.09(1H, t, J=8.0 Hz), 7.13(2H, d, J=8.0 Hz), 7.26(2H, d, J=8.0 Hz),7.33(2H, t, J=8.0 Hz), 7.40(3H, brs), 7.64(2H, d, J=8.0 Hz), 9.79(1H,s), 10.02(1H, s), 12.46(1H, s).

MS: 423(M+H)⁺ free

PRODUCTION EXAMPLE 29 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N,N-dimethyl-1,3-thiazole-5-carboxamidehydrochloride

Step 1

tert-Butyl[4-(2-{2-(acetylamino)-5-[(dimethylamino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamatewas prepared from the compound of Step 2 of Production Example 27 in asimilar manner according to Step 3 of Production Example 27.

¹H-NMR (DMSO-d₆), δ (ppm): 1.46(9H, s), 2.14(3H, s), 2.84(4H, s),2.85(6H, s), 7.01(2H, d, J=8.5 Hz), 7.31(2H, d, J=8.5 Hz), 9.21(1H,brs), 12.33(1H, brs).

MS: 433(M+H)⁺

Step 2

2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-N,N-dimethyl-1,3-thiazole-5-carboxamidewas prepared from tert-butyl[4-(2-{2-(acetylamino)-5-[(dimethylamino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamatein a similar manner according to Step 4 of Production Example 27.

¹H-NMR (DMSO-d₆), δ (ppm): 2.14(3H, s), 2.70–2.77(4H, m), 2.86(6H, s),4.83(2H, s), 6.45(2H, d, J=8.5 Hz), 6.78(2H, d, J=8.5 Hz), 12.32(1H,brs).

MS: 333(M+H)⁺

Step 3

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[(dimethylamino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from2-(acetylamino)-4-[2-(4-aminophenyl)ethyl]-N,N-dimethyl-1,3-thiazole-5-carboxamidein a similar manner according to Step 5 of Production Example 18.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.14(3H, s),2.85(6H, s), 2.89(4H, s), 7.12(2H, d, J=8.5 Hz), 7.40(2H, d, J=8.5 Hz),9.92(1H, s), 11.43(1H, brs), 12.36(1H, brs).

MS: 575(M+H)⁺

Step 4

The title compound was prepared from di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[(dimethylamino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatein a similar manner according to Step 6 of Production Example 27.

mp. 78–80° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.15(3H, s), 2.81–2.96(4H, m), 2.88(6H, s),7.11(2H, d, J=8.5 Hz), 7.18(2H, d, J=8.5 Hz), 7.38(3H, brs), 9.77(1H,s), 12.34(1H, s).

MS: 375(M+H)⁺ free

PRODUCTION EXAMPLE 30 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-benzyl-1,3-thiazole-5-carboxamidehydrochloride

Step 1

tert-Butyl[4-(2-{2-(acetylamino)-5-[(benzylamino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamatewas prepared from the compound of Step 2 of Production Example 27 in asimilar manner according to Step 3 of Production Example 27.

mp. 184–185° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.46(9H, s), 2.15(3H, s), 2.79–2.87(2H, m),3.12–3.22(2H, m), 4.37(2H, d, J=6.5 Hz), 7.02(2H, d, J=8.5 Hz),7.18–7.36(7H, m), 8.56(1H, t, J=6.5 Hz), 9.22(1H, brs), 12.37(1H, brs).

MS: 495(M+H)⁺

Step 2

2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-N-benzyl-1,3-thiazole-5-carboxamidewas prepared from tert-butyl[4-(2-{2-(acetylamino)-5-[(benzylamino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamatein a similar manner according to Step 4 of Production Example 27.

mp. 200–201° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.15(3H, s), 2.66–2.76(2H, m), 3.07–3.15(2H,m), 4.38(2H, d, J=6.0 Hz), 4.83(2H, s), 6.46(2H, d, J=8.5 Hz), 6.81(2H,d, J=8.5 Hz), 7.20–7.36(5H, m), 8.52(1H, t, J=6.0 Hz), 12.32(1H, brs).

MS: 395(M+H)⁺

Step 3

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[(benzylamino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from2-(acetylamino)-4-[2-(4-aminophenyl)ethyl]-N-benzyl-1,3-thiazole-5-carboxamidein a similar manner according to Step 5 of Production Example 18.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.15(3H, s),2.85–2.94(2H, m), 3.16–3.25(2H, m), 4.37(2H, d, J=6.0 Hz), 7.12(2H, d,J=8.5 Hz), 7.22–7.36(5H, m), 7.40(2H, d, J=8.5 Hz), 8.32(1H, s),8.54(1H, t, J=6.0 Hz), 9.94(1H, brs), 11.44(1H, brs).

MS: 637(M+H)⁺

Step 4

The title compound was prepared from di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[(benzylamino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatein a similar manner according to Step 6 of Production Example 27.

mp. 128–130° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.17(3H, s), 2.85–2.96(2H, m), 3.16–3.27(2H,m), 4.36(2H, d, J=6.0 Hz), 7.12(2H, d, J=8.5 Hz), 7.17–7.35(7H, m),7.40(3H, brs), 8.66(1H, t, J=6.0 Hz), 9.78(1H, s), 12.38(1H, s).

MS: 437(M+H)⁺ free

PRODUCTION EXAMPLE 31 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-(4-nitrobenzyl)-1,3-thiazole-5-carboxamidehydrochloride

Step 1

A mixture of2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylicacid (100 mg), (4-nitrobenzyl)amine hydrochloride (46.5 mg),1-hydroxybenzotriazole (36.7 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (40.2 mg) in DMF (2 ml)was stirred at ambient temperature for 73 hours. The reaction mixturewas poured into saturated NaHCO₃, and extracted with CHCl₃. The organiclayer was washed with water and brine, dried over anhydrous MgSO₄, andconcentrated in vacuo to givetert-butyl{4-[2-(2-(acetylamino)-5-{[(4-nitrobenzyl)amino]carbonyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamate(123.7 mg) as a pale yellow solid.

mp. 204–205° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.46(9H, s), 2.16(3H, s), 2.77–2.91(2H, m),3.12–3.27(2H, m), 4.49(2H, d, J=5.5 Hz), 7.01(2H, d, J=8.5 Hz), 7.32(2H,d, J=8.5 Hz), 7.52(2H, d, J=8.5 Hz), 8.21(2H, d, J=8.5 Hz), 8.68(1H, t,J=5.5 Hz), 9.21(1H, s), 12.40(1H, s).

MS: 540(M+H)⁺

Step 2

tert-Butyl{4-[2-(2-(acetylamino)-5-{[(4-nitrobenzyl)amino]carbonyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamate(135 mg) and TFA (2 ml) were combined at 0° C. The reaction mixture wasstirred at room temperature for an hour, and concentrated in vacuo. Theresidue was dissolved in MeOH and CHCl₃, and made basic (pH=8) by1N—NaOH. The mixture was concentrated in vacuo. The residual solid waswashed with water to give2-(acetylamino)-4-[2-(4-aminophenyl)ethyl]-N-(4-nitrobenzyl)-1,3-thiazole-5-carboxamide(92.5 mg) as a pale yellow solid.

mp. 120–121° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 2.65–2.81(2H, m), 3.04–3.21(2H,m), 4.49(2H, d, J=5.5 Hz), 5.65(2H, brs), 6.54(2H, d, J=8.0 Hz),6.86(2H, d, J=8.0 Hz), 7.54(2H, d, J=8.5 Hz), 8.21(2H, d, J=8.5 Hz),8.67(1H, t, J=5.5 Hz), 12.39(1H, s).

MS: 440(M+H)⁺

Step 3

2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-N-(4-nitrobenzyl)-1,3-thiazole-5-carboxamide(83 mg), N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (58.6mg) and THF (1 ml) were combined under N₂ atmosphere. The reactionmixture was stirred at r.t. for 2 hours, and concentrated in vacuo. Theresidual solid was washed with AcOEt to give di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{[(4-nitrobenzyl)amino]carbonyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamate(95.4 mg) as an off-white solid.

mp. 251–253° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.38(9H, s), 1.51(9H, s), 2.16(3H, s),2.81–2.98(2H, m), 3.16–3.29(2H, m), 4.49(2H, d, J=5.5 Hz), 7.12(2H, d,J=8.0 Hz), 7.40(2H, d, J=8.0 Hz), 7.53(2H, d, J=8.5 Hz), 8.20(2H, d,J=8.5 Hz), 8.67(1H, t, J=5.5 Hz), 9.93(1H, s), 11.44(1H, s), 12.42(1H,s).

MS: 682(M+H)⁺

Step 4

Di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{[(4-nitrobenzyl)amino]carbonyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamate(70 mg) and 4N HCl in 1,4-dioxane solution (1.5 ml) were combined underN₂ atmosphere. The reaction mixture was stirred at r.t. for 14 hours.The solvent was removed in vacuo. The residue was washed with AcOEt togive2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-(4-nitrobenzyl)-1,3-thiazole-5-carboxamidehydrochloride (63.7 mg) as a pale green solid.

mp. 138–140° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.17(3H, s), 2.81–3.00(2H, m), 3.17–3.30(2H,m), 4.48(2H, d, J=5.5 Hz), 7.12(2H, d, J=8.0 Hz), 7.25(2H, d, J=8.0 Hz),7.40(3H, s), 7.55(2H, d, J=8.0 Hz), 8.21(2H, d, J=8.0 Hz), 8.80(1H, t,J=5.5 Hz), 9.81(1H, s), 12.42(1H, s).

MS: 482(M+H)⁺ free

PRODUCTION EXAMPLE 32 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[4-(methylsulfonyl)benzyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

A mixture of2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylicacid (120 mg), [4-(methylthio)benzyl]amine (45.4 mg),1-hydroxybenzotriazole (44 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (59.6 mg) inDMF (2 ml) was stirred at r.t. for 17 hours. The reaction mixture waspoured into saturated NaHCO₃, and extracted with CHCl₃. The organiclayer was washed with water and brine, dried over anhydrous MgSO₄, andconcentrated in vacuo. The residue was purified by preparative silicagel chromatography with CHCl₃/AcOEt (1:1) as an eluent to givetert-butyl(4-{2-[2-(acetylamino)-5-({[4-(methylthio)benzyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamate(163.5 mg) as an off-white solid.

mp. 182–183° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.46(9H, s), 2.15(3H, s), 2.45(3H, s),2.77–2.91(2H, m), 3.09–3.24(2H, m), 4.32(2H, d, J=5.5 Hz), 7.02(2H, d,J=8.5 Hz), 7.22(4H, s), 7.33(2H, d, J=8.5 Hz), 8.54(1H, t, J=5.5 Hz),9.22(1H, s), 12.36(1H, s).

MS: 541(M+H)⁺

Step 2

Potassium peroxymonosulfate (264 mg) was suspended in water (1 ml) andTHF (1 ml), and then tert-butyl(4-{2-[2-(acetylamino)-5-({[4-(methylthio)benzyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamate(155 mg) in THF (2 ml) was added dropwise to the suspension at 0° C. Thereaction mixture was stirred at r.t. for an hour, and then water wasadded to the suspension. The solution was extracted with AcOEt (twice).The combined organic layer was washed with brine, dried over anhydrousMgSO₄, and concentrated in vacuo to give tert-butyl(4-{2-[2-(acetylamino)-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamate(140.6 mg) as an off-white solid.

mp. 192.5–193° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.46(9H, s), 2.16(3H, s), 2.73–2.90(2H, m),3.11–3.27(2H, m), 3.18(3H, s), 4.47(2H, d, J=5.5 Hz), 7.03(2H, d, J=8.5Hz), 7.33(2H, d, J=8.5 Hz), 7.53(2H, d, J=8.5 Hz), 7.89.(2H, d, J=8.5Hz), 8.68(1H, t, J=5.5 Hz), 9.22(1H, s), 12.39(1H, s).

MS: 573(M+H)⁺

Step 3

2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-N-[4-(methylsulfonyl)benzyl]-1,3-thiazole-5-carboxamidewas prepared in a similar manner according to Step 2 of ProductionExample 31.

mp. 78–80° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 2.65–2.80(2H, m), 3.04–3.22(2H,m), 3.19(3H, s), 4.46(2H, d, J=5.5 Hz), 4.82(2H, s), 6.46(2H, d, J=8.0Hz), 6.81(2H, d, J=8.0 Hz), 7.53(2H, d, J=8.0 Hz), 7.89(2H, d, J=8.0Hz), 8.63(1H, t, J=5.5 Hz), 12.39(1H, s).

MS: 473(M+H)⁺

Step 4

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.16(3H, s),2.81–2.98(2H, m), 3.18(3H, s), 3.18–3.29(2H, m), 4.46(2H, d, J=5.5 Hz),7.14(2H, d, J=8.5 Hz), 7.41(2H, d, J=8.5 Hz), 7.54(2H, d, J=8.5 Hz),7.88(2H, d, J=8.5 Hz), 8.67(1H, t, J=5.5 Hz), 9.94(1H, s), 11.44(1H, s),12.41(1H, s).

MS: 715(M+H)⁺

Step 5

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

mp. 94–96° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.17(3H, s), 2.85–2.99(2H, m), 3.19(3H, s),3.19–3.30(2H, m), 4.46(2H, d, J=5.5 Hz), 7.13(2H, d, J=8.5 Hz), 7.25(2H,d, J=8.5 Hz), 7.40(3H, s), 7.54(2H, d, J=8.5 Hz), 7.89(2H, d, J=8.5 Hz),8.78(1H, t, J=5.5 Hz), 9.80(1H, s), 12.41(1H, s).

MS: 515(M+H)⁺ free

PRODUCTION EXAMPLE 33 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[4-(trifluoromethyl)benzyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

tert-Butyl(4-{2-[2-(acetylamino)-5-({[4-(trifluoromethyl)benzyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamatewas prepared from2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylicacid in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (DMSO-d₆), δ (ppm): 1.46(9H, s), 2.16(3H, s), 2.73–2.92(2H, m),3.12–3.25(2H, m), 4.45(2H, d, J=5.5 Hz), 7.01(2H, d, J=8.5 Hz), 7.33(2H,d, J=8.5 Hz), 7.47(2H, d, J=8.5 Hz), 7.69(2H, d, J=8.5 Hz), 8.64(1H, t,J=5.5 Hz), 9.22(1H, s), 12.39(1H, s).

MS: 563(M+H)⁺

Step 2

2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-N-[4-(trifluoromethyl)benzyl]-1,3-thiazole-5-carboxamidewas prepared in a similar manner according to Step 2 of ProductionExample 31.

mp. 199–201° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.10(3H, s), 2.63–2.78(2H, m), 3.02–3.18(2H,m), 4.44(2H, d, J=5.5 Hz), 4.81(2H, s), 6.46(2H, d, J=8.0 Hz), 6.81(2H,d, J=8.0 Hz), 7.49(2H, d, J=8.0 Hz), 7.69(2H, d, J=8.0 Hz), 8.44(1H, t,J=5.5 Hz), 12.39(1H, s).

MS: 463(M+H)⁺

Step 3

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[4-(trifluoromethyl)benzyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

mp. 188–190° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.16(3H, s),2.83–2.97(2H, m), 3.17–3.29(2H, m), 4.44(2H, d, J=5.5 Hz), 7.12(2H, d,J=8.5 Hz), 7.40(2H, d, J=8.5 Hz), 7.48(2H, d, J=8.0 Hz), 7.69(2H, d,J=8.0 Hz), 8.63(1H, t, J=5.5 Hz), 9.94(1H, s), 11.44(1H, s), 12.40(1H,s).

MS: 705(M+H)⁺

Step 4

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

mp. 156–158° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.17(3H, s), 2.82–2.99(2H, m), 3.18–3.31(2H,m), 4.44(2H, d, J=5.5 Hz), 7.12(2H, d, J=8.0 Hz), 7.25(2H, d, J=8.0 Hz),7.40(3H, s), 7.51(2H, d, J=8.0 Hz), 7.71(2H, d, J=8.0 Hz), 8.76(1H, t,J=5.5 Hz), 9.81(1H, s), 12.41(1H, s).

MS: 505(M+H)⁺ free

PRODUCTION EXAMPLE 34 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-(3-pyridinyl)-1,3-thiazole-5-carboxamidedihydrochloride

Step 1

2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-1,3-thiazole-5-carboxylicacid was prepared from2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylicacid in a similar manner according to Step 2 of Production Example 31.

mp. 211.5–212° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.15(3H, s), 2.67–2.80(2H, m), 3.09–3.23(2H,m), 6.51(2H, d, J=8.0 Hz), 6.85(2H, d, J=8.0 Hz), 12.44(1H, brs).

MS: 306(M+H)⁺

Step 2

2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-1,3-thiazole-5-carboxylicacid (106 mg) was suspended in THF (2 ml) under N₂ atmosphere.Bis(trimethylsilyl)acetamide (0.253 ml) was added to the suspension atr.t., and the mixture was stirred at r.t. for 15 minutes. Then,N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (119 mg) wasadded to the solution at r.t. The reaction mixture was stirred at r.t.for 20 hours, and concentrated in vacuo. The residue was dissolved inCHCl₃. The organic solution was washed with 1N-HCl, water and brine,dried over anhydrous MgSO₄, and concentrated in vacuo. The residualsolid was washed with ethyl ether to give2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino](tert-butoxycarbonyl)iminomethyl}amino)phenyl]ethyl}-1,3-thiazole-5-carboxylicacid (115.8 mg) as a pale brown solid.

15 mp. 221.5–223° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.44(18H, brs), 2.16(3H, s), 2.91(2H, t,J=7.0 Hz), 3.26(2H, t, J=7.0 Hz), 7.17(2H, d, J=8.5 Hz), 7.43(2H, d,J=8.5 Hz), 9.95(1H, brs), 11.43(1H, brs), 12.48(1H, s).

MS: 548(M+H)⁺

Step 3

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[(3-pyridinylamino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared in a similar manner according to Step 1 of ProductionExample 32.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.19(3H, s),2.87–3.00(2H, m), 3.19–3.32(2H, m), 7.16(2H, d, J=8.5 Hz), 7.35(1H, dd,J=8.5, 4.5 Hz), 7.41(2H, d, J=8.5 Hz), 8.07(1H, m), 8.28(1H, dd, J=4.5,1.5 Hz), 8.81(1H, d, J=1.5 Hz), 9.93(1H, s), 10.11(1H, s), 11.43(1H, s),12.51(1H, s).

MS: 624(M+H)⁺

Step 4

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.21(3H, s), 2.84–3.07(2H, m), 3.19–3.39(2H,m), 7.13(2H, d, J=7.5 Hz), 7.28(2H, d, J=7.5 Hz), 7.45(3H, brs),7.37–8.81(4H, m), 9.93(1H, s), 10.75(1H, s), 12.61(1H, s).

MS: 424(M+H)⁺ free

PRODUCTION EXAMPLE 35 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-(4-phenoxybenzyl)-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{[(4-phenoxybenzyl)amino]carbonyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (DMSO-d₆), δ (ppm): 1.38(9H, s), 1.51(9H, s), 2.15(3H, s),2.81–2.97(2H, m), 3.13–3.28(2H, m), 4.35(2H, d, J=5.5 Hz), 6.97(4H, d,J=8.5 Hz), 7.11(1H, t, J=8.5 Hz), 7.13(2H, d, J=8.5 Hz), 7.29–7.41(6H,m), 8.54(1H, t, J=5.5 Hz), 9.93(1H, s), 11.44(1H, brs), 12.37(1H, brs).

MS: 729(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.17(3H, s), 2.81–3.00(2H, m), 3.13–3.30(2H,m), 4.35(2H, d, J=5.5 Hz), 6.98(4H, d, J=8.5 Hz), 7.12(2H, d, J=8.5 Hz),7.13(1H, t, J=8.5 Hz), 7.25(2H, d, J=8.5 Hz), 7.32(2H, d, J=8.5 Hz),7.40(2H, t, J=8.5 Hz), 7.46(3H, brs), 8.67(1H, t, J=5.5 Hz), 9.92(1H,s), 12.39(1H, brs).

MS: 529(M+H)⁺ free

PRODUCTION EXAMPLE 36 Synthesis of ethyl4-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}carbonyl)-1-piperazinecarboxylate

Step 1

Ethyl4-[(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)carbonyl]-1-piperazinecarboxylatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (DMSO-d₆), δ (ppm): 1.17(3H, t, J=7.0 Hz), 1.39(9H, brs),1.50(9H, brs), 2.15(3H, s), 2.90(4H, m), 3.38(8H, brs), 4.03(2H, q,J=7.0 Hz), 7.12(2H, d, J=8.5 Hz), 7.41(2H, d, J=8.5 Hz), 9.94(1H, s),11.46(1H, brs), 12.40(1H, brs).

MS: 688(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 2of the following Production Example 48.

mp. 180–182.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.18(3H, t, J=7.0 Hz), 2.07(3H, s), 2.77(4H,s), 3.43(8H, brs), 4.05(2H, q, J=7.0 Hz), 6.89(2H, d, J=7.5 Hz),7.02(2H, d, J=7.5 Hz).

MS: 488(M+H)⁺

PRODUCTION EXAMPLE 37 Synthesis ofN-{5-[(4-acetyl-1-piperazinyl)carbonyl]-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide

Step 1

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[(4-acetyl-1-piperazinyl)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, brs), 1.50(9H, brs), 1.98(3H, s),2.15(3H, s), 2.90(4H, m), 3.40(8H, brs), 7.13(2H, d, J=8.5 Hz), 7.41(2H,d, J=8.5 Hz), 9.93(1H, s), 11.43(1H, brs), 12.40(1H, brs).

MS: 658(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 2of the following Production Example 48.

mp. 206–207.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.01(3H, s), 2.05(3H, s), 2.73(4H, s),3.42(8H, brs), 6.77–7.08(4H, m).

MS: 458(M+H)⁺

PRODUCTION EXAMPLE 38 Synthesis ofN-(4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-{[4-(methylsulfonyl)-1-piperazinyl]carbonyl}-1,3-thiazol-2-yl)acetamidehydrochloride

Step 1

Di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{[4-(methylsulfonyl)-1-piperazinyl]carbonyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.15(3H, s),2.89(3H, s), 2.82–2.96(4H, m), 3.01–3.13(4H, m), 3.44–3.59(4H, m),7.14(2H, d, J=8.5 Hz), 7.42(2H, d, J=8.5 Hz), 9.94(1H, s), 11.44(1H,brs), 12.40(1H, brs).

MS: 694(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

mp. 118–119° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 2.90(3H, s), 2.83–2.98(4H, m),3.06–3.18(4H, m), 3.50–3.61(4H, m), 7.12(2H, d, J=8.5 Hz), 7.21(2H, d,J=8.5 Hz), 7.43(3H, s), 9.90(1H, s), 12.41(1H, s).

MS: 494(M+H)⁺ free

PRODUCTION EXAMPLE 39 Synthesis ofN-[4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-(4-thiomorpholinylcarbonyl)-1,3-thiazol-2-yl]acetamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-(4-thiomorpholinylcarbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.15(3H, s),2.45–2.61(4H, m), 2.79–2.99(4H, m), 3.55–3.70(4H, m), 7.13(2H, d, J=8.5Hz), 7.41(2H, d, J=8.5 Hz), 9.92(1H, s), 11.44(1H, brs), 12.38(1H, brs).

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

mp. 134–135.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 2.47–2.62(4H, m), 2.80–3.00(4H,m), 3.59–3.73(4H, m), 7.12(2H, d, J=8.5 Hz), 7.20(2H, d, J=8.5 Hz),7.39(3H, s), 9.80(1H, s), 12.38(1H, s).

MS: 433(M+H)⁺ free

PRODUCTION EXAMPLE 40 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[(1,1-dioxido-4-thiomorpholinyl)carbonyl]-1,3-thiazol-2-yl}acetamidehydrochloride

Step 1

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[(1,1-dioxido-4-thiomorpholinyl)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from the compound obtained in Step 1 of Production Example39 in a similar manner according to Step 2 of Production Example 32.

mp. 270–271.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.15(3H, s),2.85–2.96(4H, m), 3.09–3.21(4H, m), 3.69–3.83(4H, m), 7.13(2H, d, J=8.5Hz), 7.40(2H, d, J=8.5 Hz), 9.93(1H, s), 11.47(1H, brs), 12.42(1H, brs).

MS: 665(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

mp. 185–186° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 2.92(4H, s), 3.11–3.28(4H, m),3.76–3.91(4H, m), 7.12(2H, d, J=8.5 Hz), 7.22(2H, d, J=8.5 Hz), 7.40(3H,s), 9.84(1H, s), 12.40(1H, s).

MS: 465(M+H)⁺ free

PRODUCTION EXAMPLE 41 Synthesis of ethyl1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}carbonyl)-4-piperidinecarboxylatehydrochloride

Step 1

Ethyl1-{[2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl]carbonyl}-4-piperidinecarboxylatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (DMSO-d₆), δ (ppm): 1.17(3H, t, J=7.01 Hz), 1.32–1.56(2H, m),1.39(9H, s), 1.50(9H, s), 1.73–1.89(2H, m), 2.15(3H, s), 2.44–2.64(1H,m), 2.80–3.01(6H, m), 3.74–3.93(2H, m), 4.06(2H, q, J=7.0 Hz), 7.11(2H,d, J=8.5 Hz), 7.41(2H, d, J=8.5 Hz), 9.93(1H, s), 11.45(1H, brs),12.36(1H, brs).

MS: 687(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.18(3H, t, J=7.0 Hz), 1.29–1.54(2H, m),1.73–1.93(2H, m), 2.15(3H, s), 2.44–2.71(1H, m), 2.79–3.09(6H, m),3.79–3.96(2H, m), 4.09(2H, q, J=7.0 Hz), 7.11(2H, d, J=8.5 Hz), 7.19(2H,d, J=8.5 Hz), 7.40(3H, s), 9.83(1H, s), 12.37(1H, s).

MS: 487(M+H)⁺ free

PRODUCTION EXAMPLE 42 Synthesis of1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}carbonyl)-4-piperidinecarboxamidehydrochloride

Step 1

Ethyl1-[(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)carbonyl]-4-piperidinecarboxylate(277.9 mg), 1N-NaOH (1.01 ml) and 1,4-dioxane (3 ml) were combined at 0°C., and the reaction mixture was stirred at r.t. for 3 hours. Themixture was neutrallized with 1N-HCl, and the organic solvent wasevaporated in vacuo. The residual aqueous solution was extracted withAcOEt. The organic layer was washed with water and brine, dried overanhydrous MgSO₄, and concentrated in vacuo to give1-[(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)carbonyl]-4-piperidinecarboxylicacid (262.4 mg) as a pale yellow amorphous substance.

¹H-NMR (DMSO-d₆), δ (ppm): 1.28–1.59(2H, m), 1.45(18H, s), 1.72–1.90(2H,m), 2.15(3H, s), 2.40–2.59(1H, m), 2.78–3.03(6H, m), 3.77–3.94(2H, m),7.12(2H, d, J=8.5 Hz), 7.40(2H, d, J=8.5 Hz), 9.94(1H, brs), 11.44(1H,brs), 12.36(1H, s).

MS: 659(M+H)⁺

Step 2

Di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{[4-(aminocarbonyl)-1-piperidinyl]carbonyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared in a similar manner according to Step 1 of ProductionExample 32.

¹H-NMR (DMSO-d₆), δ (ppm): 1.29–1.55(2H, m), 1.39(9H, s), 1.50(9H, s),1.62–1.79(2H, m), 2.14(3H, s), 2.22–2.43(1H, m), 2.78–2.99(6H, m),3.89–4.07(2H, m), 6.80(1H, s), 7.14(2H, d, J=8.5 Hz), 7.27(1H, s),7.41(2H, d, J=8.5 Hz), 9.93(1H, s), 11.44(1H, brs), 12.36(1H, s).

MS: 658(M+H)⁺

Step 3

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.27–1.52(2H, m), 1.64–1.79(2H, m),2.15(3H, s), 2.25–2.44(2H, m), 2.76–3.02(6H, m), 6.82(1H, br), 7.11(2H,d, J=8.5 Hz), 7.19(2H, d, J=8.5 Hz), 7.34(1H, br), 7.41(4H, s), 9.83(1H,s), 12.36(1H, s).

MS: 458(M+H)⁺ free

PRODUCTION EXAMPLE 43 Synthesis of1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}carbonyl)-N-methyl-4-piperidinecarboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({4-[(methylamino)carbonyl]-1-piperidinyl}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 1 of Production Example42 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (DMSO-d₆), δ (ppm): 1.30–1.75(4H, m), 1.39(9H, s), 1.50(9H, s),2.14(3H, s), 2.22–2.42(1H, m), 2.55(2H, d, J=4.5 Hz), 2.78–2.99(6H, m),3.90–4.03(2H, m), 7.14(2H, d, J=8.5 Hz), 7.41(2H, d, J=8.5 Hz), 7.73(1H,q, J=4.5 Hz), 9.93(1H, s), 11.43(1H, brs), 12.36(1H, brs).

MS: 672(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.29–1.52(2H, m), 1.60–1.77(2H, m),2.15(3H, s), 2.55(3H, d, J=4.5 Hz), 2.78–2.98(6H, m), 3.88–4.06(3H, m),7.11(2H, d, J=8.5 Hz), 7.19(2H, d, J=8.5 Hz), 7.37(4H, br), 7.81(1H, m),9.75(1H, s), 12.36(1H, s).

MS: 472(M+H)⁺ free

PRODUCTION EXAMPLE 44 Synthesis of1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}carbonyl)-N,N-dimethyl-4-piperidinecarboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({4-[(dimethylamino)carbonyl]-1-piperidinyl}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 1 of Production Example42 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (DMSO-d₆), δ (ppm): 1.30–1.70(4H, m), 1.39(9H, s), 1.50(9H, s),2.15(3H, s), 2.80(3H, s), 2.79–3.01(7H, m), 3.00(3H, s), 3.88–4.06(2H,m), 7.13(2H, d, J=8.5 Hz), 7.41(2H, d, J=8.5 Hz), 9.92(1H, s), 11.42(1H,brs), 12.36(1H, brs).

MS: 686(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.27–1.51(2H, m), 1.55–1.72(2H, m),2.15(3H, s), 2.80(3H, s), 2.81–3.00(6H, m), 3.03(3H, s), 3.89–3.96(3H,m), 7.11(2H, d, J=8.5 Hz), 7.20(2H, d, J=8.5 Hz), 7.37(4H, br), 9.79(1H,s), 12.36(1H, s).

MS: 486(M+H)⁺

PRODUCTION EXAMPLE 45 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-phenyl-1,3-thiazol-2-yl}acetamidehydrochloride

Step 1

2-Oxo-3-phenylpropanoic acid (20 g), DMF (100 ml) and DBU (18.2 ml) werecombined at 0° C. under N₂ atmosphere, and the mixture was stirred at 0°C. for an hour. Then iodomethane (15.2 ml) was added to the solution at0° C. The reaction mixture was stirred at r.t. for 3 hours, and pouredinto 1N-HCl. The mixture was extracted with AcOEt (twice). The combinedorganic layer was washed with brine, dried over anhydrous MgSO₄, andconcentrated in vacuo. The residue was purified by flash columnchromatography over silica gel with CHCl₃/AcOEt (30:1) as an eluent, andtriturated with IPE/n-Hexane to give methyl 2-oxo-3-phenylpropanoate(11.2 g) as a pale yellow wax.

¹H-NMR (CDCl₃), δ (ppm): 3.92(3H, s), 6.42(1H, s), 6.53(1H, s),7.28–7.42(3H, m), 7.77(2H, dd, J=8.5, 1.5 Hz).

MS: 179(M+H)⁺

Step 2

Methyl 2-oxo-3-phenylpropanoate (11 g), pyridinium tribromide (24.1 g),CH₂Cl₂ (490 ml) and AcOH (1.5 ml) were combined at 0° C. under N₂atmosphere. The reaction mixture was stirred at 0° C. for 1.5 hours,poured into water and participated. The organic layer was dried overanhydrous MgSO₄, and concentrated in vacuo. The residual oil wasdissolved in EtOH (190 ml), and then thiourea (6.11 g) was added to thesolution. The reaction mixture was refluxed for an hour under N₂atmosphere. After cooled to 0° C., water was added to the solution. Theprecipitate was filtered in vacuo to give methyl2-amino-5-phenyl-1,3-thiazole-4-carboxylate (6.63 g) as an off-whitesolid.

mp. 208–208.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 3.67(3H, s), 7.38–7.53(5H, m).

MS: 235(M+H)⁺

Step 3

Methyl 2-amino-5-phenyl-1,3-thiazole-4-carboxylate (3 g) was dissolvedin pyridine (30 ml), and then acetyl chloride (2.73 ml) was addeddropwise to the solution at 0° C. under N₂ atmosphere. The reactionmixture was stirred at r.t. for 1.5 hours. Water was added to thesolution at 0° C. The precipitate was filtered in vacuo, and the solidwas washed with ethyl ether to give methyl2-(acetylamino)-5-phenyl-1,3-thiazole-4-carboxylate (2.37 g) as a palebrown solid.

mp. 224.5–225.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 3.68(3H, s), 7.39–7.57(5H, m),12.56(1H, s).

MS: 277(M+H)⁺

Step 4

Methyl 2-(acetylamino)-5-phenyl-1,3-thiazole-4-carboxylate (2.34 g) wassuspended in THF (23 ml), and then lithium aluminium hydride (482 mg)was added portionwise to the solution at 0° C. The reaction mixture wasstirred at 0° C. for 1.5 hours and quenched with MeOH. AcOEt and 1N HClwere added to the mixture, and the mixture was extracted. The aqueouslayer was extracted with AcOEt (twice). The combined organic layer waswashed with brine, dried over anhydrous MgSO₄, and concentrated invacuo. The residual solid was dissolved in MeOH (5 ml) and CHCl₃ (90ml). Then manganase(IV) oxide (11 g) was added to the solution under N₂atmosphere. The reaction mixture was stirred at r.t. for 13 hours, andfiltered through a celite pad. The filtrate was concentrated in vacuo.The residue was purified by flash column chromatography over silica gelwith CHCl₃/MeOH (20:1) as an eluent to giveN-(4-formyl-5-phenyl-1,3-thiazol-2-yl)acetamide (705.2 mg) as a brownamorphous substance.

¹H-NMR (DMSO-d₆), δ (ppm): 2.19(3H, s), 7.49–7.58(3H, m), 7.60–7.69(2H,m), 9.78(1H, s), 12.60(1H, s).

MS: 247(M+H)⁺

Step 5

1-(Bromomethyl)-4-nitrobenzene (1.03 g), triphenylphosphine (1.25 g) andDMF (14 ml) were combined under N₂ atmosphere. The reaction mixture wasstirred at r.t. for 6 hours. Then potassium tert-butoxide (629 mg) andN-(4-formyl-5-phenyl-1,3-thiazol-2-yl)acetamide (690 mg) were added tothe mixture, and the mixture was stirred at r.t. for 13 hours. Thereaction mixture was poured into ice-water, and extracted with AcOEt.The organic layer was washed with 1N-HCl, water and brine, dried overanhydrous MgSO₄, and concentrated in vacuo. The residue was purified byflash column chromatography over silica gel with CHCl₃/AcOEt (1:1) as aneluent to give a mixture ofN-{4-[(E)-2-(4-nitrophenyl)vinyl]-5-phenyl-1,3-thiazol-2-yl}acetamideandN-{4-[(Z)-2-(4-nitrophenyl)vinyl]-5-phenyl-1,3-thiazol-2-yl}acetamide(E:Z=2:1) (1.02 g) as an orange wax.

¹H-NMR (DMSO-d₆), δ (ppm): 2.13(3H×⅓, s), 2.19(3H×⅔, s), 6.65(1H×⅓, d,J=12.5 Hz), 6.78(1H×⅓, d, J=12.5 Hz), 7.32(1H×⅔, d, J=15.5 Hz),7.39–7.59(5H+1H×⅔, m), 7.61(2H×⅓, d, J=9.0 Hz), 7.77(2H×⅔, d, J=9.0 Hz),8.13(2H×⅓, d, J=9.0 Hz), 8.19(2H×⅔, d, J=9.0 Hz), 12.33(1H, brs).

MS: 366(M+H)⁺

Step 6

A mixture ofN-{4-[(E)-2-(4-nitrophenyl)vinyl]-5-phenyl-1,3-thiazol-2-yl}acetamideandN-{4-[(Z)-2-(4-nitrophenyl)vinyl]-5-phenyl-1,3-thiazol-2-yl}acetamide(E:Z=2:1) (600 mg), 10% palladium carbon (657 mg), MeOH (6 ml), THF (6ml) and AcOH (1 ml) were combined. The reaction mixture was stirredunder 3 atm H₂ at r.t. for 3.5 hours, and filtered through a celite pad.The filtrate was concentrated in vacuo. 1N-NaOH was added to theresidue, and the mixture was extracted with AcOEt. The organic layer waswashed with water and brine, dried over MgSO₄, and concentrated in vacuoto giveN-{4-[2-(4-aminophenyl)ethyl]-5-phenyl-1,3-thiazol-2-yl}acetamide (528.6mg) as a pale brown amorphous substance.

¹H-NMR (DMSO-d₆), δ (ppm): 2.15(3H, s), 2.80(4H, s), 4.82(2H, s),6.45(2H, d, J=8.5 Hz), 6.78(2H, d, J=8.5 Hz), 7.21–7.44(5H, m),12.18(1H, brs).

MS: 338(M+H)⁺

Step 7

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-phenyl-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.21(9H, s), 1.44(9H, s), 2.15(3H, s),2.83–2.98(4H, m), 7.10(2H, d, J=8.5 Hz), 7.22–7.47(7H, m), 9.92(1H, s),11.43(1H, s), 12.22(1H, s).

MS: 580(M+H)⁺

Step 8

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

mp. 80–82° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 2.83–3.08(4H, m), 7.11(2H, d,J=8.0 Hz), 7.21(2H, d, J=8.0 Hz), 7.29–7.54(8H, m), 9.94(1H, s),12.22(1H, brs).

MS: 380(M+H)⁺ free

PRODUCTION EXAMPLE 46 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-benzyl-1,3-thiazol-2-yl}acetamidehydrochloride

Step 1

To a suspension of copper(II) bromide (9.75 g) in AcOEt (150 ml) wasadded a solution of ethyl 2-oxo-4-phenylbutanoate (3 g) in 75 ml ofCHCl₃. The reaction mixture was refluxed for 23 hours, cooled to r.t.,and filtered through a short pad of silica gel eluting withAcOEt/n-hexane (1:1). The solvent was removed in vacuo to give ethyl3-bromo-2-oxo-4-phenylbutanoate (4.2 g) as a yellow liquid.

¹H-NMR (CDCl₃), δ (ppm): 1.37(3H, t, J=7.0 Hz), 3.25(1H, dd, J=14.5, 7.5Hz), 3.54(1H, dd, J=14.5, 7.5 Hz), 4.35(2H, q, J=7.0 Hz), 5.27(1H, d,J=7.5 Hz), 7.18–7.41(5H, m).

Step 2

Ethyl 3-bromo-2-oxo-4-phenylbutanoate (5.8 g) was dissolved in EtOH (110ml), and then thiourea (3.1 g) was added to the solution. The reactionmixture was refluxed for 2 hours under N₂ atmosphere. The cooledreaction mixture was evaporated in vacuo. The residual solid wassuspended (pH=8) in saturated NaHCO₃ and water. The solid was collectedby filtration, and purified by flash column chromatography over silicagel with CHCl₃/MeOH (10:1) as an eluent to give ethyl2-amino-5-benzyl-1,3-thiazole-4-carboxylate (808.2 mg) as a yellow wax.

¹H-NMR (DMSO-d₆), δ (ppm): 1.25(3H, t, J=7.0 Hz), 4.21(2H, q, J=7.0 Hz),4.33(2H, s), 7.02(2H, s), 7.11–7.39(5H, m).

MS: 263(M+H)⁺

Step 3

Ethyl 2-(acetylamino)-5-benzyl-1,3-thiazole-4-carboxylate was preparedin a similar manner according to Step 3 of Production Example 45.

mp. 178–180° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.28(3H, t, J=7.0 Hz), 2.09(3H, s), 4.28(2H,q, J=7.0 Hz), 4.48(2H, s), 7.19–7.39(5H, m), 12.41(1H, s).

MS: 305(M+H)⁺

Step 4

Ethyl 2-(acetylamino)-5-benzyl-1,3-thiazole-4-carboxylate (1.0 g) wasdissolved in THF(20 ml), and then lithium borohydride (124 mg) was addedportionwise to the solution at 0° C. The reaction mixture was refluxedfor 4.5 hours and quenched with MeOH. The mixture was concentrated invacuo, and purified by flash column chromatography over silica gel withCHCl₃/MeOH (20:1) as an eluent. The residual amorphous substance wasdissolved in MeOH (1 ml) and CHCl₃ (8 ml). Then manganase(IV) oxide(1.26 g) was added to the solution under N₂ atmosphere. The reactionmixture was stirred at r.t. for 12 hours, and filtered through a celitepad. The filtrate was concentrated in vacuo. The residue was purified byflash column chromatography over silica gel with CHCl₃/MeOH (20:1) as aneluent to give N-(5-benzyl-4-formyl-1,3-thiazol-2-yl)acetamide (251 mg)as a pale yellow solid.

mp. 191–192.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.12(3H, s), 4.53(2H, s), 7.19–7.40(5H, m),10.04(1H, s), 12.34(1H, s).

MS: 261(M+H)⁺

Step 5

N-{5-Benzyl-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamidewas prepared in a similar-manner according to Step 5 of ProductionExample 45.

Z:E=2:1

¹H-NMR (DMSO-d₆), δ (ppm): 2.08(3H×⅔, s), 2.12(3H×⅓, s), 4.08(2H×⅔, s),4.34(2H×⅓, s), 6.72(1H×⅔, d, J=12.5 Hz), 6.86(1H×⅔, d, J=12.5 Hz),7.17–7.39(5H+2H×⅓, m), 7.66(2H×⅔, d, J=9.0 Hz), 7.92(2H×⅓, d, J=9.0 Hz),8.14(2H×⅔, d, J=9.0 Hz), 8.22(2H×⅓, d, J=9.0 Hz), 11.85(1H×⅔, s),12.16(1H×⅓, s).

MS: 380(M+H)⁺

Step 6

N-{4-[2-(4-Aminophenyl)ethyl]-5-benzyl-1,3-thiazol-2-yl}acetamide wasprepared in a similar manner according to Step 6 of Production Example45.

¹H-NMR (DMSO-d₆), δ (ppm): 2.07(3H, s), 2.59–2.85(4H, m), 3.85(2H, s),4.84(2H, s), 6.46(2H, d, J=8.5 Hz), 6.78(2H, d, J=8.5 Hz), 7.07(2H, d,J=8.0 Hz), 7.16–7.31(3H, m), 11.96(1H, s).

MS: 352(M+H)⁺

Step 7

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-benzyl-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.07(3H, s),2.85(4H, s), 3.89(2H, s), 7.05–7.33(7H, m), 7.42(2H, d, J=8.5 Hz),9.95(1H, s), 11.44(1H, s), 11.99(1H, s).

MS: 594(M+H)⁺

Step 8

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

mp. 97–99° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.86(4H, s), 3.93(2H, s),7.05–7.37(9H, m), 7.47(3H, s), 9.98(1H, s), 12.01(1H, brs).

MS: 394(M+H)⁺ free

PRODUCTION EXAMPLE 47 Synthesis ofN-{4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide

Step 1

3-(4-Mercaptophenyl)propanoic acid (5 g), K₂CO₃ (11.4 g) and DMF (30 ml)were combined, and iodomethane (5.12 ml) was added dropwise to themixture at 0° C. under N₂ atmosphere. The reaction mixture was stirredat r.t. for 13 hours, and poured into ice-water. The mixture wasextracted with AcOEt. The organic layer was washed with water (twice)and brine, dried over anhydrous MgSO₄, and concentrated in vacuo to givemethyl 3-[4-(methylthio)phenyl]propanoate (4.19 g) as pale yellow oil.

¹H-NMR (CDCl₃), δ (ppm): 2.47(3H, s), 2.61(2H, t, J=8.0 Hz), 2.91(2H, t,J=8.0 Hz), 3.67(3H, s), 7.12(2H, d, J=8.5 Hz), 7.20(2H, d, J=8.5 Hz).

Step 2

Sodium methoxide, 28% solution in MeOH (3.67 ml), was added dropwise tothe mixture of methyl 3-[4-(methylthio)phenyl]propanoate (4 g) anddiethyl oxalate (5.17 ml) at 0° C. with stirring. The reaction mixturewas stirred at 65° C. for 30 minutes under reduced pressure. 15% AqueousH₂SO₄ (35 ml) was added to the mixture, and the mixture was refluxed for15 hours. After cooled to r.t., the mixture was extracted with AcOEt.The organic layer was washed with water and brine, dried over anhydrousMgSO₄, and concentrated in vacuo. The residual oil was dissolved in EtOH(20 ml), and concentrated H₂SO₄ (0.4 ml) was added dropwise to thesolution. The reaction mixture was refluxed for 2 hours. After cooled tor.t., EtOH was removed in vacuo. AcOEt and water were added to theresidue, and extracted. The organic layer was washed with water andbrine, dried over anhydrous MgSO₄, and concentrated in vacuo. Theresidue was purified by flash column chromatography over silica gel withn-hexane/AcOEt (6:1) as an eluent to give ethyl4-[4-(methylthio)phenyl]-2-oxobutanoate (2.43 g) as a yellow liquid.

¹H-NMR (CDCl₃), δ (ppm): 1.35(3H, t, J=7.0 Hz), 2.46(3H, s), 2.92(2H, t,J=7.0 Hz), 3.16(2H, t, J=7.0 Hz), 4.31(2H, q, J=7.0 Hz), 7.13(2H, d,J=8.5 Hz), 7.20(2H, d, J=8.5 Hz).

Step 3

Ethyl 3-bromo-4-[4-(methylthio)phenyl]-2-oxobutanoate was prepared in asimilar manner according to Step 1 of Production Example 46.

¹H-NMR (CDCl₃), δ (ppm): 1.37(3H, t, J=7.0 Hz), 2.47(3H, s), 3.20(1H,dd, J=14.5, 7.5 Hz), 3.49(1H, dd, J=14.5, 7.5 Hz), 4.35(2H, q, J=7.0Hz), 5.22(1H, d, J=7.5 Hz), 7.17(2H, d, J=8.5 Hz), 7.20(2H, d, J=8.5Hz).

Step 4

Ethyl 2-amino-5-[4-(methylthio)benzyl]-1,3-thiazole-4-carboxylate wasprepared in a similar manner according to Step 2 of Production Example46.

¹H-NMR (DMSO-d₆), δ (ppm): 1.25(3H, t, J=7.0 Hz), 2.44(3H, s), 4.20(2H,q, J=7.0 Hz), 4.28(2H, s), 7.02(2H, s), 7.19(4H, s).

MS: 309(M+H)⁺

Step 5

Ethyl2-(acetylamino)-5-[4-(methylthio)benzyl]-1,3-thiazole-4-carboxylate wasprepared in a similar manner according to Step 3 of Production Example45.

mp. 205–206° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.28(3H, t, J=7.0 Hz), 2.09(3H, s), 2.45(3H,s), 4.27(2H, q, J=7.0 Hz), 4.43(2H, s), 7.22(4H, s), 12.41(1H, s).

MS: 351(M+H)⁺

Step 6

N-{4-Formyl-5-[4-(methylthio)benzyl]-1,3-thiazol-2-yl}acetamide wasprepared in a similar manner according to Step 4 of Production Example46.

¹H-NMR (DMSO-d₆), δ (ppm): 2.12(3H, s), 2.45(3H, s), 4.48(2H, s),7.23(4H, s), 10.03(1H, s), 12.33(1H, s).

MS: 307(M+H)⁺

Step 7

N-{5-[4-(Methylthio)benzyl]-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamidewas prepared in a similar manner according to Step 5 of ProductionExample 45.

Z:E=2:1

¹H-NMR (DMSO-d₆), δ (ppm): 2.08(3H×⅔, s), 2.12(3H×⅓, s), 2.44(3H, s),4.04(2H×⅔, s), 4.30(2H×⅓, s), 6.71(1H×⅔, d, J=12.5 Hz), 6.84(1H×⅔, d,J=12.5 Hz), 7.18(4H×⅔, s), 7.23(4H×⅓, s), 7.24(1H×⅓, d, J=15.5 Hz),7.40(1H×⅓, d, J=15.5 Hz), 7.65(2H×⅔, d, J=9.0 Hz), 7.92(2H×⅓, d, J=9.0Hz), 8.12(2H×⅔, d, J=9.0 Hz), 8.22(2H×⅓, d, J=9.0 Hz), 11.85(1H×⅔, brs),12.16(1H×⅓, brs).

MS: 426(M+H)⁺

Step 8

N-{5-[4-(Methylsulfonyl)benzyl]-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamidewas prepared in a similar manner according to Step 2 of ProductionExample 32.

Z:E=2:1

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H×⅔, s), 2.13(3H×⅓, s), 3.18(3H, s),4.24(2H×⅔, s), 4.49(2H×⅓, s), 6.73(1H×⅔, d, J=12.5 Hz), 6.86(1H×⅔, d,J=12.5 Hz), 7.33(1H×⅓, d, J=15.5 Hz), 7.41–7.97(5/3H, m), 7.48(2H×⅔, d,J=9.0 Hz), 7.55(2H×⅓, d, J=9.0 Hz), 7.65(2H×⅔, d, J=9.0 Hz), 7.85(2H×⅔,d, J=9.0 Hz), 8.14(2H×⅔, d, J=9.0 Hz), 8.22(2H×⅓, d, J=9.0 Hz),11.90(1H×⅔, s), 12.22(1H×⅓, s).

MS: 458(M+H)⁺

Step 9

The title compound was prepared in a similar manner according to Step 6of Production Example 45.

¹H-NMR (DMSO-d₆), δ (ppm): 2.08(3H, s), 2.58–2.87(4H, m), 3.18(3H, s),3.98(2H, s), 4.85(2H, s), 6.46(2H, d, J=8.5 Hz), 6.77(2H, d, J=8.5 Hz),7.27(2H, d, J=8.5 Hz), 7.82(2H, d, J=8.5 Hz), 12.02(1H, s).

MS: 430(M+H)⁺

PRODUCTION EXAMPLE 48 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide

Step 1

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from the compound obtained in Example 47 in a similarmanner according to Step 3 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.08(3H, s),2.86(4H, s), 3.16(3H, s), 4.03(2H, s), 7.13(2H, d, J=8.5 Hz), 7.33(2H,d, J=8.5 Hz), 7.43(2H, d, J=8.5 Hz), 7.81(2H, d, J=8.5 Hz), 9.97(1H, s),11.45(1H, s), 12.05(1H, s).

MS: 672(M+H)⁺

Step 2

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamate(953 mg) and 4N HCl in 1,4-dioxane solution (10 ml) were combined underN₂ atmosphere. The reaction mixture was stirred at r.t. for 7 hours. Thesolvent was removed in vacuo. The residue was dissolved in water andAcOEt. The solution was made basic (pH=8) by saturated NaHCO₃. Theprecipitate was filtered in vacuo to giveN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(667.7 mg) as a pale yellow solid.

mp. 228–229.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.08(3H, s), 2.79(4H, m), 3.18(3H, s),4.05(2H, s), 6.72(2H, d, J=8.0 Hz), 6.99(2H, d, J=8.0 Hz), 7.37(2H, d,J=8.5 Hz), 7.84(2H, d, J=8.5 Hz).

MS: 472(M+H)⁺

PRODUCTION EXAMPLE 49 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamidehydrochloride

The title compound was prepared from the compound obtained in Step 1 ofProduction Example 48 in a similar manner according to Step 4 ofProduction Example 31.

mp. 107–110° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.87(4H, s), 3.19(3H, s),4.08(2H, s), 7.13(2H, d, J=8.5 Hz), 7.25(2H, d, J=8.5 Hz), 7.40(2H, d,J=8.5 Hz), 7.44(3H, s), 7.85(2H, d, J=8.5 Hz), 9.94(1H, s), 12.05(1H,brs).

MS: 472(M+H)⁺ free

PRODUCTION EXAMPLE 50 Synthesis ofN-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide

Step 1

To a ice-cold solution ofN-{4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(247.6 mg) in acetone (4.8 ml) was added benzoyl isothiocyanate (94.1mg), and the mixture was stirred at r.t. for 1 hour. Water was added tothe mixture, and the mixture was extracted with AcOEt. The organic layerwas washed with water and brine, dried over anhydrous MgSO₄, andconcentrated in vacuo. The residual amorphous substance was dissolved inEtOH (5 ml), and 6N-NaOH (0.288 ml) was added to the solution at 0° C.The reaction mixture was stirred at r.t. for 2 hours, and neutralizedwith 1N-HCl at 0° C. The mixture was extracted with AcOEt. The organiclayer was washed with water and brine, dried over anhydrous MgSO₄, andconcentrated in vacuo. The residue was solidified with ethyl ether togiveN-{4-(2-{4-[(aminocarbonothioyl)amino]phenyl}ethyl)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(290.7 mg) as an off-white solid.

mp. 102–103° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.85(4H, s), 3.18(3H, s),4.03(2H, s), 7.11(2H, d, J=8.5 Hz), 7.30(2H, d, J=8.5 Hz), 7.36(2H, d,J=8.5 Hz), 7.84(2H, d, J=8.5 Hz), 9.64(1H, s), 12.04(1H, s).

MS: 489(M+H)⁺

Step 2

A mixture ofN-(4-(2-{4-[(aminocarbonothioyl)amino]phenyl}ethyl)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl)acetamide(281.8 mg), methyl iodide (0.0431 ml) and MeOH (3 ml) was refluxed for3.5 hours. The reaction mixture was concentrated in vacuo. The residuewas diluted with AcOEt and stirred for 30 minutes. The precipitatedcrystals were filtered and washed with AcOEt to give methylN-[4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]imidothiocarbamatehydroiodide (291.5 mg) as an off-white amorphous solid.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.68(3H, s), 2.90(4H, s),3.18(3H, s), 4.07(2H, s), 7.22(2H, d, J=8.5 Hz), 7.32(2H, d, J=8.5 Hz),7.39(2H, d, J=8.5 Hz), 7.86(2H, d, J=8.5 Hz), 9.22(1H, brs), 11.11(1H,brs), 12.03(1H, s).

MS: 503(M+H)⁺ free

Step 3

The title compound was prepared in a similar manner according to thefollowing Production Example 58.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.87(4H, s), 3.19(3H, s),4.08(2H, s), 7.12(2H, d, J=8.5 Hz), 7.23(2H, d, J=8.5 Hz), 7.41(2H, d,J=8.5 Hz), 7.85(2H, d, J=8.5 Hz), 8.92(2H, brs), 12.03(1H, brs).

MS: 487(M+H)⁺

PRODUCTION EXAMPLE 51 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(ethylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamidehydrochloride

Step 1

Ethyl 3-[4-(ethylthio)phenyl]propanoate was prepared from4-(2-carboxyethyl)thiophenol in a similar manner according to Step 1 ofProduction Example 47.

¹H-NMR (CDCl₃), δ (ppm): 1.23(3H, t, J=7.0 Hz), 1.29(3H, t, J=7.0 Hz),2.60(2H, t, J=8.5 Hz), 2.82–2.99(4H, m), 4.12(2H, q, J=7.0 Hz), 7.12(2H,d, J=8.5 Hz), 7.26(2H, d, J=8.5 Hz).

Step 2

Ethyl 4-[4-(ethylthio)phenyl]-2-oxobutanoate was prepared in a similarmanner according to Step 2 of Production Example 47.

¹H-NMR (CDCl₃), δ (ppm): 1.31(3H, t, J=7.0 Hz), 1.36(3H, t, J=7.0 Hz),2.92(2H, q, J=7.0 Hz), 2.93(2H, t, J=7.0 Hz), 3.16(2H, t, J=7.0 Hz),4.27(2H, q, J=7.0 Hz), 7.08(2H, d, J=9.0 Hz), 7.26(2H, d, J=9.0 Hz).

Step 3

Ethyl 3-bromo-4-[4-(ethylthio)phenyl]-2-oxobutanoate was prepared in asimilar manner according to Step 1 of Production Example 46.

¹H-NMR (CDCl₃), δ (ppm): 1.31(3H, t, J=7. 5 Hz), 1.38(3H, t, J=7.5 Hz),2.93(2H, q, J=7.5 Hz), 3.21(1H, dd, J=14.5, 7.5 Hz), 3.49(1H, dd,J=14.5, 7.5 Hz), 4.35(2H, q, J=7.5 Hz), 5.23(1H, t, J=7.5 Hz), 7.16(2H,d, J=8.5 Hz), 7.27(2H, d, J=8.5 Hz).

Step 4

Ethyl 2-amino-5-[4-(ethylthio)benzyl]-1,3-thiazole-4-carboxylate wasprepared in a similar manner according to Step 2 of Production Example46.

¹H-NMR (DMSO-d₆), δ (ppm): 1.22(6H, t, J=7.0 Hz), 2.94(2H, q, J=7.0 Hz),4.20(2H, q, J=7.0 Hz), 4.29(2H, s), 7.03(2H, s), 7.18(2H, d, J=8.5 Hz),7.26(2H, d, J=8.5 Hz).

MS: 323(M+H)⁺

Step 5

Ethyl 2-(acetylamino)-5-[4-(ethylthio)benzyl]-1,3-thiazole-4-carboxylatewas prepared in a similar manner according to Step 3 of ProductionExample 45.

mp. 189.5–190° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.21(3H, t, J=7.5 Hz), 1.28(3H, t, J=7.0 Hz),2.09(3H, s), 2.95(2H, q, J=7.5 Hz), 4.27(2H, q, J=7.0 Hz), 4.44(2H, s),7.22(2H, d, J=8.5 Hz), 7.26(2H, d, J=8.5 Hz), 12.42(1H, s).

MS: 365(M+H)⁺

Step 6

N-{5-[4-(Ethylthio)benzyl]-4-formyl-1,3-thiazol-2-yl}acetamide wasprepared in a similar manner according to Step 4 of Production Example46.

¹H-NMR (DMSO-d₆), δ (ppm): 1.21(3H, t, J=7.5 Hz), 2.17(3H, s), 2.95(2H,q, J=7.5 Hz), 4.49(2H, s), 7.26(4H, s), 10.03(1H, s), 12.34(1H, s).

Step 7

N-{5-[4-(Ethylthio)benzyl]-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamidewas prepared in a similar manner according to Step 5 of ProductionExample 45.

Z:E=3:2

¹H-NMR (DMSO-d₆), δ (ppm): 1.20(3H, t, J=7.5 Hz), 2.08(3H×⅗, s),2.12(3H×⅖, s), 2.93(2H, q, J=7.5 Hz), 4.05(2H×⅗, s), 4.31(2H×⅖, s),6.71(1H×⅗, d, J=12.5 Hz), 6.84(1H×⅗, d, J=12.5 Hz), 7.13–8.16(6H+⅘H, m),8.12(2H×⅗, d, J=9.0 Hz), 8.22(2H×⅖, d, J=9.0 Hz), 11.86(1H×⅗, brs),12.18(1H×⅖, brs).

MS: 440(M+H)⁺

Step 8

N-{5-[4-(Ethylsulfonyl)benzyl]-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamidewas prepared in a similar manner according to Step 2 of ProductionExample 32.

Z:E=3:2

¹H-NMR (DMSO-d₆), δ (ppm): 1.06(3H, t, J=7.5 Hz), 2.09(3H×⅗, s),2.13(3H×⅖, s), 3.25(2H, q, J=7.5 Hz), 4.24(2H×⅗, s), 4.50(2H×⅖, s),6.73(1H×⅗, d, J=12.5 Hz), 6.87(1H×⅗, d, J=12.5 Hz), 7.43–8.31(8H+⅘H, m),11.91(1H×⅗, brs), 12.22(1H×⅖, brs).

MS: 472(M+H)⁺

Step 9

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[4-(ethylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.05(3H, t, J=7.5 Hz), 1.39(9H, s), 1.51(9H,s), 2.09(3H, s), 2.85(4H, s), 3.22(2H, q, J=7.5 Hz), 4.04(2H, s),7.11(2H, d, J=8.5 Hz), 7.32(2H, d, J=8.5 Hz), 7.43(2H, d, J=8.5 Hz),7.77(2H, d, J=8.5 Hz), 9.97(1H, s), 11.44(1H, s), 12.05(1H, s).

MS: 686(M+H)⁺

Step 10

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.07(3H, t, J=7.5 Hz), 2.09(3H, s), 2.86(4H,s), 3.26(2H, q, J=7.5 Hz), 4.09(2H, s), 7.13(2H, d, J=8.0 Hz), 7.24(2H,d, J=8.0 Hz), 7.44(3H, brs), 7.60(2H, d, J=8.0 Hz), 7.81(2H, d, J=8.0Hz), 9.89(1H, s), 12.05(1H, brs).

MS: 486(M+H)⁺ free

PRODUCTION EXAMPLE 52 Synthesis of ethyl{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}carbamate

Step 1

N-{4-[2-(4-Aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(300 mg) was dissolved in THF (3 ml) under N₂ atmosphere. Thendi(tert-butyl)dicarbonate (168 mg) in THF (3 ml) was added to thesolution at r.t. The reaction mixture was stirred at r.t. for 14 hours,and concentrated in vacuo. The residue was purified by flash columnchromatography over silica gel with CHCl₃/AcOEt (1:1) as an eluent togive tert-butyl[4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamate(248.5 mg) as an off-white amorphous substance.

¹H-NMR (DMSO-d₆), δ (ppm): 1.47(9H, s), 2.08(3H, s), 2.82(4H, s),3.16(3H, s), 3.99(2H, s), 7.00(2H, d, J=8.5 Hz), 7.25(2H, d, J=8.5 Hz),7.33(2H, d, J=8.5 Hz), 7.79(2H, d, J=8.5 Hz), 9.24(1H, s), 12.03(1H, s).

MS: 530(M+H)⁺

Step 2

tert-Butyl[4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamate(230 mg), 1N-NaOH (1.09 ml) and EtOH (5 ml) were combined, and themixture was refluxed for 16 hours. After cooled to r.t., the organicsolvent was removed in vacuo. The aqueous solution was neutrallized with1N-HCl, and extracted with AcOEt. The organic layer was washed withwater and brine, dried over anhydrous MgSO₄, and concentrated in vacuo.The residue was purified by preparative silica gel chromatography withCHCl₃/MeOH (30:1) as an eluent to give tert-butyl[4-(2-{2-amino-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamate(151.2 mg) as an off-white amorphous substance.

¹H-NMR (DMSO-d₆), δ (ppm): 1.47(9H, s), 2.58–2.82(4H, m), 3.16(3H, s),3.84(2H, s), 6.73(2H, s), 7.02(2H, d, J=8.5 Hz), 7.21(2H, d, J=8.5 Hz),7.33(2H, d, J=8.5 Hz), 7.77(2H, d, J=8.5 Hz), 9.24(1H, s).

MS: 488(M+H)⁺

Step 3

tert-Butyl[4-(2-{2-amino-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamate(140 mg) was dissolved in pyridine (2 ml) under N₂ atmosphere. Then,ethyl chloroformate (30.2 ml) was added to the solution at 0° C. Thereaction mixture was stirred at r.t. for 2 hours, and concentrated invacuo. The residue was dissolved in AcOEt, and washed with 1N-HCl, waterand brine. The organic layer was dried over anhydrous MgSO₄, andconcentrated in vacuo to give ethyl{4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}carbamate(155.8 mg) as an off-white amorphous substance.

¹H-NMR (DMSO-d₆), δ (ppm): 1.21(3H, t, J=7.0 Hz), 1.47(9H, s), 2.79(4H,s), 3.16(3H, s), 3.97(2H, s), 4.14(2H, q, J=7.0 Hz), 7.00(2H, d, J=8.5Hz), 7.24(2H, d, J=8.5 Hz), 7.33(2H, d, J=8.5 Hz), 7.79(2H, d, J=8.5Hz), 9.54(1H, s), 11.64(1H, brs).

MS: 560(M+H)⁺

Step 4

Ethyl{4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}carbamate(140 mg) and 4N HCl in 1,4-dioxane solution (3 ml) were combined underN₂ atmosphere. The reaction mixture was stirred at r.t. for 2 hours. Thesolvent was removed in vacuo. The residue was dissolved in water andAcOEt. The mixture was made basic (pH=8) by 1N-NaOH. The organic layerwas washed with water and brine, dried over anhydrous MgSO₄, andconcentrated in vacuo to give ethyl{4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}carbamate(125.6 mg) as an off-white amorphous substance.

¹H-NMR (DMSO-d₆), δ (ppm): 1.21(3H, t, J=7.0 Hz), 2.60–2.80(4H, m),3.18(3H, s), 3.97(2H, s), 4.14(2H, q, J=7.0 Hz), 4.85(2H, brs), 6.46(2H,d, J=8.5 Hz), 6.77(2H, d, J=8.5 Hz), 7.29(2H, d, J=8.5 Hz), 7.82(2H, d,J=8.5 Hz), 11.62(1H, brs).

MS: 460(M+H)⁺

Step 5

Di-tert-butyl((Z)-{[4-(2-{2-[(ethoxycarbonyl)amino]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.21(3H, t, J=7.0 Hz), 1.39(9H, s), 1.51(9H,s), 2.84(4H, s), 3.16(3H, s), 4.01(2H, s), 4.14(2H, q, J=7.0 Hz),7.13(2H, d, J=8.5 Hz), 7.33(2H, d, J=8.5 Hz), 7.43(2H, d, J=8.5 Hz),7.81(2H, d, J=8.5 Hz), 9.97(1H, s), 11.45(1H, s), 11.61(1H, brs).

MS: 702(M+H)⁺

Step 6

The title compound was prepared in a similar manner according to Step 2of Production Example 48.

¹H-NMR (DMSO-d₆), δ (ppm): 1.17(3H, t, J=7.0 Hz), 2.57(4H, s), 3.17(3H,s), 4.01(2H, q, J=7.0 Hz), 4.03(2H, s), 7.00(4H, s), 7.42(2H, d, J=8.5Hz), 7.83(2H, d, J=8.5 Hz).

MS: 502(M+H)⁺

PRODUCTION EXAMPLE 53 Synthesis ofN-{4-{2-[4-(aminomethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide

Step 1

[4-(Methoxycarbonyl)benzyl](triphenyl)phosphonium bromide (4.81 g) andDMF (60 ml) were combined under N₂ atmosphere. Then potassiumtert-butoxide (1.32 g) andN-{4-formyl-5-[4-(methylthio)benzyl]-1,3-thiazol-2-yl}acetamide (3 g)were added to the suspension at 0° C. The reaction mixture was stirredat r.t. for 18 hours, poured into ice-water, and extracted with AcOEt.The organic layer was washed with water and brine, dried over anhydrousMgSO₄, and concentrated in vacuo. The residue was purified by flashcolumn chromatography over silica gel with CHCl₃/AcOEt (2:1) as aneluent. The solid was suspended in AcOEt, and the suspension wasfiltered. The filtrate was concentrated in vacuo to give methyl4-((Z)-2-{2-(acetylamino)-5-[4-(methylthio)benzyl]-1,3-thiazol-4-yl}vinyl)benzoate(4.16 g) as a yellow amorphous substance.

¹H-NMR (DMSO-d₆), δ (ppm): 2.08(3H, s), 2.43(3H, s), 3.84(3H, s),3.96(2H, s), 6.67(1H, d, J=12.5 Hz), 6.74(1H, d, J=12.5 Hz), 7.11(2H, d,J=8.5 Hz), 7.17(2H, d, J=8.5 Hz), 7.50(2H, d, J=8.5 Hz), 7.85(2H, d,J=8.5 Hz), 11.88(1H, s).

MS: 439(M+H)⁺

Step 2

Methyl4-{(Z)-2-(2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}vinyl)benzoatewas prepared in a similar manner according to Step 2 of ProductionExample 32.

Z:E=2:1

¹H-NMR (DMSO-d₆), δ (ppm): 2.08(3H×⅔, s), 2.12(3H×⅓, s), 3.18(3H, s),3.84(3H×⅔, s), 3.86(3H×⅓, s), 4.15(2H×⅔, s), 4.47(2H×⅓, s), 6.68(1H×⅔,d, J=12.5 Hz), 6.77(1H×⅔, d, J=12.5 Hz), 7.30(1H×⅓, d, J=15.5 Hz),7.43(2H, d, J=8.5 Hz), 7.50–7.97(19/3H, m), 11.93(1H×⅔, s), 12.19(1H×⅓,s).

MS: 471(M+H)⁺

Step 3

Methyl4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)benzoatewas prepared in a similar manner according to Step 6 of ProductionExample 45.

mp. 209–210° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.94(4H, m), 3.17(3H, s),3.84(3H, s), 4.01(2H, s), 7.25(2H, d, J=8.5 Hz), 7.28(2H, d, J=8.5 Hz),7.76(2H, d, J=8.5 Hz), 7.85(2H, d, J=8.5 Hz), 12.05(1H, brs).

MS: 473(M+H)⁺

Step 4

To a stirred solution of methyl4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)benzoate(2 g) in dry THF (40 ml) was added dropwise 1.0M diisobutylaluminiumhydride solution in toluene (14.8 ml) at −78° C. under N₂ atmosphere.The reaction mixture was stirred at r.t. for 4 hours, and then quenchedwith MeOH. AcOEt and 1N-HCl were added to the mixture, and extracted.The organic layer was washed with brine, dried over anhydrous MgSO₄, andconcentrated in vacuo. The residue was purified by flash columnchromatography over silica gel with CHCl₃/MeOH (20:1) as an eluent togiveN-{4-{2-[4-(hydroxymethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(552.3 mg) as a colorless solid.

mp. 209.5–211° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.86(4H, s), 3.17(3H, s),4.01(2H, s), 4.46(2H, d, J=5.5 Hz), 5.12(1H, t, J=5.5 Hz), 7.09(2H, d,J=8.0 Hz), 7.20(2H, d, J=8.0 Hz), 7.28(2H, d, J=8.5 Hz), 7.80(2H, d,J=8.5 Hz), 12.04(1H, brs).

MS: 445(M+H)⁺

Step 5

N-{4-{2-[4-(Hydroxymethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(539.5 mg), CH₂Cl₂ (5 ml) and DMF (5 ml) were combined under N₂atmosphere. Then, Et₃N (0.211 ml) and MsCl (0.108 ml) were added to thesuspension at 0° C. The reaction mixture was stirred at r.t. for 3.5hours. The reaction mixture was poured into water, and extracted withCHCl₃. The organic layer was washed with brine, dried over anhydrousMgSO₄, and concentrated in vacuo. The residual solid was washed withethyl ether to giveN-{4-{2-[4-(chloromethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(537.5 mg) as an off-white solid.

mp. 202–203° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.88(4H, s), 3.17(3H, s),4.01(2H, s), 4.73(2H, s), 7.15(2H, d, J=8.0 Hz), 7.30(2H, d, J=8.5 Hz),7.34(2H, d, J=8.0 Hz), 7.81(2H, d, J=8.5 Hz), 12.05(1H, brs).

MS: 463(M+H)⁺

Step 6

N-{4-{2-[4-(Chloromethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(150 mg) was suspended in CH₃CN (6 ml), and then 28% ammonia solution(0.4 ml) was added to the suspension at 0° C. The reaction mixture wasstirred at r.t. for 16 hours, and concentrated in vacuo. The residualsolid was washed with water, and purified by preparative silica gelchromatography with CHCl₃/MeOH (10:1) as an eluent to giveN-{4-{2-[4-(aminomethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(32.1 mg) as a pale yellow amorphous substance.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.85(4H, s), 3.17(3H, s),3.69(2H, s), 4.01(2H, s), 7.07(2H, d, J=8.0 Hz), 7.21(2H, d, J=8.0 Hz),7.29(2H, d, J=8.5 Hz), 7.80(2H, d, J=8.5 Hz).

MS: 444(M+H)⁺

PRODUCTION EXAMPLE 54 Synthesis ofN-{4-{2-[4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide

A mixture ofN-{4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}-acetamide(200 mg), 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole (62 mg),concentrated HCl (0.064 ml) and 2-methoxyethanol (3 ml) was stirred at120° C. for 13 hours under N₂ atmosphere. After cooled to r.t., thereaction mixture was made basic with saturated NaHCO₃. The mixture wasextracted with AcOEt. The organic layer was dried over anhydrous MgSO₄,and concentrated in vacuo. The residue was purified by preparativesilica gel chromatography with CHCl₃/MeOH (10:1) as an eluent to giveN-{4-{2-[4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(139.8 mg) as a pale yellow amorphous substance.

¹H-NMR (DMSO-d₆), δ (ppm): 2.08(3H, s), 2.82(4H, s), 3.16(3H, s),3.17–3.34(4H, m), 3.98(2H, s), 6.99(2H, d, J=8.5 Hz), 7.25(2H, d, J=8.5Hz), 7.45(2H, brd, J=8.5 Hz), 7.80(2H, d, J=8.5 Hz), 9.24(1H, brs),12.04(1H, s).

MS: 515(M+H)⁺

PRODUCTION EXAMPLE 55 Synthesis ofN-{4-{2-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide

A mixture ofN-(4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl)acetamide(150 mg), ethyl 2-(methylthio)-4,5-dihydro-1H-imidazole-1-carboxylate(78.9 mg), ACOH (0.3 ml) and EtOH (3 ml) was refluxed for 7 hours underN₂ atmosphere. After cooled to r.t., the reaction mixture was made basicwith saturated NaHCO₃. The mixture was extracted with AcOEt. The organiclayer was washed with brine, dried over anhydrous MgSO₄, andconcentrated in vacuo. The residue was purified by preparative silicagel chromatography with CHCl₃/MeOH (10:1) as an eluent. The amorphoussubstance was solidified with ethyl ether to giveN-{4-{2-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(17.9 mg) as an off-white amorphous solid.

mp. 139–140° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.08(3H, s), 2.71–2.87(4H, m), 3.18(3H, s),3.25–3.41(4H, m), 4.03(2H, s), 6.95(4H, s), 7.32(2H, d, J=8.5 Hz),7.82(2H, d, J=8.5 Hz).

MS: 498(M+H)⁺

PRODUCTION EXAMPLE 56 Synthesis ofN-{4-{2-[4-(ethanimidoylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide

N-{4-[2-(4-Aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(200 mg), methyl ethanimidothioate hydroiodide (202 mg) and MeOH (4 ml)were combined under N₂ atmosphere. The reaction mixture was refluxed for3 hours. After cooled to room temperature, the mixture was concentratedin vacuo. The residue was purified by preparative NH silica gelchromatography with CHCl₃/MeOH (10:1) as an eluent. The amorphoussubstance was solidified with ethyl ether to giveN-{4-{2-[4-(ethanimidoylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(102.4 mg) as a pale yellow amorphous solid.

mp. 81.5–83° C.

¹H-NMR (CDCl₃), δ (ppm): 1.83(3H, brs), 2.08(3H, s), 2.81(4H, m),3.18(3H, s), 4.02(2H, s), 6.64(2H, brd, J=8.5 Hz), 6.99(2H, d, J=8.5Hz), 7.36(2H, d, J=8.5 Hz), 7.83(2H, d, J=8.5 Hz), 12.03(1H, brs).

MS: 471(M+H)⁺

PRODUCTION EXAMPLE 57 Synthesis ofN-[4-(2-{4-[(iminomethyl)amino]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide

N-(4-[2-(4-Aminophenyl)ethyl]-1,3-thiazol-2-yl)acetamide (150 mg) wasdissolved in THF (2 ml) and pH=7 buffer (2 ml). Then, ethyl imidoformatehydrochloride (1.26 g) was added to the solution at 0° C. The reactionmixture was stirred at 0° C. for 2 hours, and concentrated in vacuo. Theresidue was purified by flash column chromatography over silica gel withCH₃CN/water (7:3) as an eluent. The oil was purified again bypreparative silica gel chromatography with CHCl₃/MeOH (5:1) as an eluentto giveN-[4-(2-{4-[(iminomethyl)amino]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide(110 mg) as pale brown oil.

¹H-NMR (DMSO-d₆), δ (ppm): 2.12(3H, s), 2.81–3.01(4H, m), 6.71(1H, s),7.09–8.00(7H, m), 12.07(1H, s).

MS: 289(M+H)⁺

PRODUCTION EXAMPLE 58 Synthesis ofN-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide

A mixture of methylN-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)imidothiocarbamatehydroiodide (100 mg), hydrazine monohydrate (0.0525 ml) and THF (3 ml)was stirred at r.t. for 95 hours. The precipitate was filtered off. Thefiltrate was concentrated in vacuo. The residue was purified bypreparative silica gel chromatography with CHCl₃/MeOH (10:1) as aneluent to giveN-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide(62.7 mg) as a pale pink solid.

mp. 216.5–218° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.12(3H, s), 2.92(4H, m), 6.75(1H, s),7.12(2H, d, J=8.5 Hz), 7.27(2H, d, J=8.5 Hz), 8.88(1H, brs), 12.07(1H,brs).

MS: 319(M+H)⁺

PRODUCTION EXAMPLE 59: Synthesis ofN-(4-{2-[4-(2-amino-2-iminoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide

Step 1

N-(4-{2-[4-(Chloromethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide wasprepared fromN-(4-{2-[4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide in asimilar manner according to Step 5 of Production Example 53.

mp. 145–146° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.82–2.99(4H, m), 4.72(2H, s),6.73(1H, s), 7.20(2H, d, J=8.0 Hz), 7.33(2H, d, J=8.0 Hz), 12.08(1H,brs).

MS: 295(M+H)⁺

Step 2

NaCN (115 mg), KI (130 mg) and water (1.8 ml) were combined, and then asolution ofN-(4-{2-[4-(chloromethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (230mg) in DMF (7 ml) was added dropwise to the mixture at 0° C. Thereaction mixture was stirred at r.t. for 19 hours, poured into water,and extracted with CHCl₃. The organic layer was washed with brine, driedover anhydrous MgSO₄ and concentrated in vacuo. The residual solid waswashed with ethyl ether to giveN-(4-{2-[4-(cyanomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide(149.1-mg) as a colorless solid.

mp. 160–161° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.82–2.97(4H, m), 3.97(2H, s),6.73(1H, s), 7.21(2H, d, J=8.5 Hz), 7.25(2H, d, J=8.5 Hz), 12.08(1H,brs).

MS: 286(M+H)⁺

Step 3

N-(4-{2-[4-(Cyanomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (600mg) was dissolved in MeOH (5 ml) and CHCl₃ (5 ml), and then HCl gas wasbubbled at 0° C. for 5 minutes with stirring. The reaction mixture wasstood for 17 hours, and concentrated in vacuo. The residual solid waswashed with ethyl ether to give methyl2-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethanimidoatehydrochloride (632.5 mg) as an off-white solid.

mp. 77–78° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.12(3H, s), 2.88(4H, s), 4.92(6H, brs),6.75(1H, s), 7.10–7.20(4H, m), 12.11(1H, brs).

MS: 318(M+H)⁺ free

Step 4

Methyl2-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethanimidoatehydrochloride (600 mg) was dissolved in EtOH (12 ml). Then ammoniumchloride (136 mg) and ammonia in methanol (2 ml) were added to thesolution. The reaction mixture was refluxed for 4 hours under N₂atmosphere. After cooled to r.t., the suspension was filtered in vacuo.The filtrate was concentrated in vacuo, and the residue was solidifiedwith EtOH/diethyl ether to giveN-(4-{2-[4-(2-amino-2-iminoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamidehydrochloride (338.6 mg) as an off-white solid.

mp. 190.5–192° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.12(3H, s), 2.89(4H, m), 3.68(2H, s),6.74(1H, s), 7.20(2H, d, J=8.0 Hz), 7.39(2H, d, J=8.0 Hz).

MS: 303(M+H)⁺ free

Step 5

N-(4-{2-[4-(2-Amino-2-iminoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamidehydrochloride (67 mg) was dissolved in water (1 ml) and CH₃CN (1 ml).The solution was made basic (pH=8) with saturated NaHCO₃, andconcentrated in vacuo. The residue was purified by preparative NH silicagel chromatography with CH₃CN/water (7:3) as an eluent to giveN-(4-{2-[4-(2-amino-2-iminoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide(26 mg) as an off-white amorphous substance.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.89(4H, m), 3.59(2H, s),6.72(1H, s), 7.20(2H, d, J=8.0 Hz), 7.30(2H, d, J=8.0 Hz), 9.38(3H,brs).

MS: 303(M+H)⁺

PRODUCTION EXAMPLE 60 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylthio)benzyl]-1,3-thiazol-2-yl}acetamide

Step 1

A mixture ofN-{5-[4-(methylthio)benzyl]-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamideandN-{5-[4-(methylthio)benzyl]-4-[(E)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide(Z:E=2:1) (570 mg) was dissolved in CH₂Cl₂ (6 ml) under N₂ atmosphere.Then m-CPBA (254 mg) was added portionwise to the solution at 0° C. Thereaction mixture was stirred at r.t. for 1.5 hours, and diluted inMeOH/CHCl₃. The organic solution was washed with 1N-Na₂CO₃, water andbrine, dried over MgSO₄, and concentrated in vacuo to give a mixture ofN-{5-[4-(methylsulfinyl)benzyl]-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamideandN-{5-[4-(methylsulfinyl)benzyl]-4-[(E)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide(Z:E=2:1) (282.8 mg) as a yellow amorphous substance.

Z:E=2:1

¹H-NMR (DMSO-d₆), 8-(ppm): 2.08(3H×⅔, s), 2.13(3H×⅓, s), 2.71(3H, s),4.18(2H×⅔, s), 4.44(2H×⅓, s), 6.73(1H×⅔, d, J=12.5 Hz), 6.87(1H×⅔, d,J=12.5 Hz), 7.34(1H×⅓, d, J=15.5 Hz), 7.41–8.17(7/3H, m), 7.41(2H×⅔, d,J=8.0 Hz), 7.50(2H×⅓, d, J=8.0 Hz), 7.63(2H×⅔, d, J=8.0 Hz), 7.93(2H×⅓,d, J=8.0 Hz), 8.14(2H×⅔, d, J=8.0 Hz), 8.22(2H×⅓, d, J=8.0 Hz),11.89(1H×⅔, s), 12.20(1H×⅓, s).

MS: 442(M+H)⁺

Step 2

N-{4-[2-(4-Aminophenyl)ethyl]-5-[4-(methylsulfinyl)benzyl]-1,3-thiazol-2-yl}acetamidewas prepared in a similar manner according to Step 6 of ProductionExample 45.

¹H-NMR (DMSO-d₆), δ (ppm): 2.08(3H, s), 2.62–2.84(4H, m), 2.70(3H, s),3.94(2H, s), 4.85(2H, s), 6.46(2H, d, J=8.5 Hz), 6.77(2H, d, J=8.5 Hz),7.23(2H, d, J=8.5 Hz), 7.58(2H, d, J=8.5 Hz), 12.00(1H, s).

MS: 414(M+H)⁺

Step 3

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[4-(methylsulfinyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.08(3H, s),2.69(3H, s), 2.86(4H, s), 3.98(2H, s), 7.12(2H, d, J=8.5 Hz), 7.26(2H,d, J=8.0 Hz), 7.43(2H, d, J=8.5 Hz), 7.57(2H, d, J=8.0 Hz), 9.95(1H, s),11.43(1H, s), 12.02(1H, s).

MS: 656(M+H)⁺

Step 4

The title compound was prepared in a similar manner according to Step 2of Production Example 48.

mp. 159.5–161° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.07(3H, s), 2.44(3H, s), 2.79(4H, s),3.86(2H, s), 6.78(2H, d, J=8.5 Hz), 7.02(2H, d, J=8.5 Hz), 7.04(2H, d,J=8.5 Hz), 7.30(2H, d, J=8.5 Hz).

MS: 440(M+H)⁺

PRODUCTION EXAMPLE 61 Synthesis ofN-{4-[4-(3-{[amino(imino)methyl]amino}propyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamidehydrochloride

Step 1

To a solution of methyl 4-{[4-(methylthio)phenyl]acetyl}benzoate (5 g)in dichloromethane (250 ml) were added acetic acid (0.65 ml) andpyridinium bromide perbromide (6.51 g) at 0° C., and the mixture wasstirred for 1 h at the same temperature. The reaction mixture was pouredinto water (250 ml) and extracted with ethyl acetate (250 ml). Theorganic layer was washed with water and brine, dried over magnesiumsulfate and evapolated. The residue was washed with diisopropylethylether and collected by filtration to give methyl4-{2-bromo[4-(methylthio)phenyl]acetyl}benzoate as an off-white solid.

¹H-NMR (CDCl₃), δ (ppm): 2.47(3H, s), 3.94(3H, s), 6.33(3H, s), 7.23(2H,d, J=8.5 Hz), 7.43(2H, d, J=8.5 Hz).

Step 2

Methyl 4-{2-amino-5-[4-(methylthio)phenyl]-1,3-thiazol-4-yl}benzoate wasprepared in a similar manner according to Step 2 of Production Example46.

¹H-NMR (DMSO-d₆), δ (ppm): 2.47(3H, s), 3.83(3H, s), 7.08–7.32(4H, m),7.52(2H, d, J=8.5 Hz), 7.85(2H, d, J=8.5 Hz).

MS: 357.1(M+H)⁺

Step 3

To a solution of methyl4-{2-amino-5-[4-(methylthio)phenyl]-1,3-thiazol-4-yl}benzoate (100 mg)in tetrahydrofuran (4 ml) was added portionwise lithium aluminiumhydride (21.3 mg), and the mixture was stirred for 1 h at 20° C. To thereaction mixture were added ethyl acetate (10 ml) and water (3 ml). Theresulting precipitate was removed by filtration, and the filtrate waswashed with brine, dried over sodium sulfate and evaporated to give(4-{2-amino-5-[4-(methylthio)phenyl]-1,3-thiazol-4-yl}phenyl)methanol asa yellow solid, that was used as crude in the next reaction.

¹H-NMR (DMSO-d₆), δ (ppm): 2.46(3H, s), 4.46(2H, d, J=6.0 Hz), 5.17(t,1H, J=5.5 Hz), 7.13(d, 2H, J=5.5 Hz), 7.17(d, 2H, J=5.5 Hz), 7.20(d, 2H,J=8.5 Hz), 7.34(d, 2H, J=8.5 Hz).

MS: 329.2(M+H)⁺

Step 4

To a suspension of(4-{2-amino-5-[4-(methylthio)phenyl]-1,3-thiazol-4-yl}phenyl)methanol(89.3 mg) in dichloromethane (1 ml) were added pyridine (0.11 ml) andacetylchloride (42.5 μl) at 0° C., and the mixture was stirred at thesame temperature for 1 hr. To the reaction mixture was added1N-hydrochloric acid (10 ml), and the mixture was extracted with ethylacetate (20 ml×2). The organic layer was washed with water and brine,dried over magnesium sulfate and evaporated to give a crude green solid(77.6 mg). To a solution of the crude green solid in dichloromethane (3ml) was added 3-chloroperbenzoic acid (80.7 mg) at 0° C., and themixture was stirred for 2 hr at 20° C. To the reaction mixture was addedsaturated sodium hydrogencarbonate aqueous solution (10 ml), and themixture was extracted with ethyl acetate (20 ml×2), washed with waterand brine, dried over magnesium sulfate, and evaporated to give4-{2-(acetylamino)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-4-yl}benzylacetate as a brown solid.

¹H-NMR (CDCl₃), δ (ppm): 1.77(3H, s), 2.14(3H, s), 3.10(3H, s), 5.12(2H,s), 7.32(2H, d, J=8.5 Hz), 7.45(2H, d, J=8.5 Hz), 7.52(2H, d, J=8.5 Hz),7.88(2H, d, J=8.5 Hz), 11.1(1H, brs).

MS: 467.0(M+Na)⁺

Step 5

To a suspension of4-(2-(acetylamino)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-4-yl)benzylacetate (1.218 g) in metanol (24 ml) was added pottasium carbonate (379mg) at 20° C., and the mixture was stirred for 1 h. To the reactionmixture was added 0.1N-hydrochloric acid (27.4 ml), and the mixture wasextracted with chloroform (500 ml), dried over magnesium sulfate andevaporated to giveN-{4-[4-(hydroxymethyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamideas a yellow solid.

¹H-NMR (CDCl₃), δ (ppm): 1.87(3H, s), 3.09(3H, s), 4.72(2H, s), 7.31(2H,d, J=8.5 Hz), 7.42(2H, d, J=8.5 Hz), 7.51(2H, d, J=8.5 Hz), 7.87(2H, d,J=8.5 Hz), 10.83(1H, brs).

MS: 425.0(M+Na)⁺

Step 6

To a solution ofN-{4-[4-(hydroxymethyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide(867.4 mg) in methanol (0.6 ml) and chloroform (10 ml) was addedmanganese(IV) oxide (6.65 g) at 20° C. under N₂ atmosphere, and themixture was stirred for 19 hrs. The reaction mixture was filteredthrough a celite pad. The filtrate was evaporeted to giveN-{4-(4-formylphenyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamideas a yellow solid, that was used as crude in the next reaction.

¹H-NMR (DMSO-d₆), δ (ppm): 2.20(3H, s), 3.26(3H, s), 7.63(2H, d, J=8.5Hz), 7.64(2H, d, J=8.0 Hz), 7.90(2H, d, J=8.0 Hz), 7.92(2H, d, J=8.5Hz), 10.00(1H, s), 12.5(1H, brs).

Step 7

To a suspension ofN-{4-(4-formylphenyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide(360 mg) in chloroform (7 ml) was added(carbethoxymethylene)triphenylphosphorane (626 mg) at 20° C., and themixture was stirred for 1 h. The reaction mixture was evaporated. Theresidue was purified by column chromatography over silica gel (150 ml)with hexane/ethyl acetate (1:1–1:2) as an eluent to give ethyl(2E)-3-(4-{2-(acetylamino)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-4-yl}phenyl)acrylateas a pale yellow solid.

¹H-NMR (CDCl₃), δ (ppm): 1.34(3H, t, J=7.0 Hz), 1.93(3H, s), 3.10(3H,s), 4.28(2H, q, J=7.0 Hz), 6.45(1H, d, J=16.1 Hz), 7.48(4H, s), 7.54(2H,d, J=8.5 Hz), 7.67(2H, d, J=16.1 Hz), 7.89(2H, d, J=8.5 Hz), 10.39(1H,s).

MS: 493.1(M+Na)⁺

Step 8

To a suspension of ethyl(2E)-3-(4-{2-(acetylamino)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-4-yl}phenyl)acrylate(306.5 mg) in tetrahydrofuran (3 ml) was added portionwise lithiumborohydride (271 mg) at 0° C., and the mixture was stirred for 6.5 h at20° C. The reaction mixture was poured into a mixture of saturatedammonium chloride aqueous solution (50 ml) and chloroform (50 ml) at 0°C. The organic layer was separeted, dried over maganesium sulfate andevaporarted to give a crude yellow solid (300 mg). The residue waspurified by column chromatography over silica gel (80 ml) withhexane/ethyl acetate (1:2–1:5) as an eluent to giveN-{4-[4-(3-hydroxypropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamideas a pale yellow solid.

¹H-NMR (CDCl₃), δ (ppm): 1.71(3H, s), 1.80–1.99(2H, m), 2.61–2.82(2H,m), 3.09(3H, s), 3.69(2H, dd, J=6.0, 10.0 Hz), 7.17(2H, d, J=8.0 Hz),7.37(2H, d, J=8.5 Hz), 7.53(2H, d, J=8.5 Hz), 7.87(2H, d, J=8.5 Hz),11.1(1H, s).

MS: 431.20(M+1)⁺

Step 9

To a solution ofN-{4-[4-(3-hydroxypropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide(75 mg) in tetrahydrofuran (0.7 ml) were added triphenylphosphine (68.5mg) and carbon tetrabromide (86.7 mg) at 0° C., and the mixture wasstirred for 1 h at 20° C. The reaction mixture was purified bypreparative thin-layer chromatography over silica gel with hexane/ethylacetate (1:2) as an eluent to giveN-{4-[4-(3-bromopropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamideas colorless oil.

¹H-NMR (DMSO-d₆), δ (ppm): 1.67(3H, s), 2.08–2.28(2H, m), 2.80(2H, t,J=7.5 Hz), 3.10(3H, s), 3.41(2H, t, J=6.5 Hz), 7.18(2H, d, J=8.0 Hz),7.39(2H, d, J=8.0 Hz), 7.53(2H, d, J=8.5 Hz), 7.87(2H, d, J=8.5 Hz),11.1(1H, s).

MS: 515.0(M+Na)⁺

Step 10

To a solution ofN-{4-[4-(3-bromopropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide(82 mg) in N,N-dimethylformamide (0.82 ml) was added phthalimidepotassium salt (30.8 mg), and the mixture was stirred for 2 hrs. at 50°C. The reaction mixture was cooled to 20° C., then water was added tothe reaction mixture, and the mixture was extracted with ethyl acetate,washed with brine, dried over magnesium sulfate and evaporated to give acrude material (92.0 mg). The crude material was purified by preparativethin-layer chromatography over silica gel to giveN-{4-{4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]phenyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide.

¹H-NMR (CDCl₃), δ (ppm): 1.72(3H, s), 1.90–2.13(2H, m), 2.60–2.79(2H,m), 3.09(3H, s), 3.74(2H, t, J=7.3 Hz), 7.18(2H, d, J=8.0 Hz), 7.37(2H,d, J=8.0 Hz), 7.52(2H, d, J=8.5 Hz), 7.66–7.78(2H, m), 7.80–7.92(4H, m),1.0(1H, s).

MS: 582.1(M+Na)⁺

Step 11

To a solution ofN-{4-(4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]phenyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl)acetamide(53.2 mg) in acetonitrile (0.5 ml) was added hydrazine monohydrate (46.1μl), and the mixture was stirred at 50° C. for 30 min. The volatileswere evaporated. To the mixture was added chloroform (1 ml), and aninsoluble material was removed by filtration. The filtrate was purifiedby preparative thin-layer chromatography over NH silica gel withchloroform/methanol (10:1) as an eluent to giveN-{4-[4-(3-aminopropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamideas a yellow solid.

¹H-NMR (DMSO-d₆), δ (ppm): 1.69(3H, s), 1.69–1.88(2H, m), 2.60–2.74(2H,m), 2.76(2H, t, J=7.0 Hz), 3.09(3H, s), 7.15(2H, d, J=8.5 Hz), 7.36(2H,d, J=8.5 Hz), 7.53(2H, d, J=8.5 Hz), 7.86(2H, d, J=8.5 Hz).

MS: 428.2(M−H)⁻

Step 12

Di-tert-butyl((E)-{[3-(4-{2-(acetylamino)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-4-yl}phenyl)propyl]amino}methylidene)biscarbamatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

¹H-NMR (CDCl₃), δ (ppm): 1.49(9H, s), 1.50(9H, s), 1.87–1.97(2H, m),2.01(3H, s), 2.69(2H, t, J=8.1 Hz), 3.09(3H, s), 3.41–3.54(2H, m),7.16(2H, d, J=8.1 Hz), 7.36(2H, d, J=8.1 Hz), 7.54(2H, d, J=8.5 Hz),7.87(2H, d, J=8.4 Hz), 8.38(1H, t, J=5.1 Hz), 9.87(1H, brs), 11.5(1H,s).

MS: 694.2(M+Na)⁺

Step 13

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.72–1.85(2H, m), 2.19(3H, s), 2.58–2.66(2H,m), 3.08–3.18(2H, m), 3.25(3H, s), 6.65–7.58(4H, brs), 7.21(2H, d, J=8.4Hz), 7.36(2H, d, J=8.1 Hz), 7.56(2H, d, J=8.4 Hz), 7.67(1H, t, J=5.1Hz), 7.89(2H, d, J=8.4 Hz), 12.4(1H, s).

MS: 472.1(M+H)⁺ free

PRODUCTION EXAMPLE 62 Synthesis ofN-{4-(2-{4-[(aminooxy)methyl]phenyl}ethyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide

Step 1

Methyl4-((E)-2-{2-(acetylamino)-5-[4-(methylthio)phenyl]-1,3-thiazol-4-yl}vinyl)benzoatewas prepared fromN-{5-[4-(methylthio)phenyl]-4-formyl-1,3-thiazol-2-yl}acetamide in asimilar manner according to Step 1 of Production Example 53.

¹H-NMR (DMSO-d₆), δ (ppm): 2.12(3H×⅓, s), 2.19(3H×⅔, s), 2.54(3H, s),3.85(3H, s), 6.55(1H×⅓, d, J=12.6 Hz), 6.73(1H×⅓, d, J=12.6 Hz),7.17–7.72(8H+2H×⅔, m), 7.84(2H×⅓, d, J=8.5 Hz), 7.93(2H×⅔, d, J=8.5 Hz),12.31(1H, brs).

MS: 423.1(M−H)⁻

Step 2

Methyl4-((E)-2-{2-(acetylamino)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-4-yl}vinyl)benzoatewas prepared in a similar manner according to Step 2 of ProductionExample 32.

¹H-NMR (DMSO-d₆), δ (ppm): 2.15(3H×⅕, s), 2.21(3H×⅘, s), 3.24(3H×⅕, s),3.30(3H×⅘, s), 3.84(3H×⅕, s), 3.85(3H×⅘, s), 6.64(1H×⅕, d, J=12.6 Hz),6.81(1H×⅕, d, J=12.6 Hz), 7.31(1H×⅘, d, J=15.6 Hz), 7.52(1H×⅘, d, J=15.6Hz), 7.30–8.11(8H, m), 12.24(1H×⅕, s), 12.49(1H×⅘, s).

MS: 479.0(M+Na)⁺

Step 3

Methyl4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-4-yl}ethyl)benzoatewas prepared in a similar manner according to Step 6 of ProductionExample 45.

¹H-NMR (DMSO-d₆), δ (ppm): 2.31(3H, s), 2.97–3.07(4H, m), 3.08(3H, s),3.91(3H, s), 7.09(2H, d, J=8.1 Hz), 7.32(2H, d, J=8.1 Hz), 7.87(4H, d,J=8.1 Hz), 8.75(1H, s).

MS: 481.0(M+Na)⁺

Step 4

N-{4-{2-[4-(Hydroxymethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamidewas prepared in a similar manner according to Step 4 of ProductionExample 53.

¹H-NMR (DMSO-d₆), δ (ppm): 2.17(3H, s), 2.96(4H, s), 3.24(3H, s),4.43(2H, s), 7.06(2H, d, J=8.1 Hz), 7.18(2H, d, J=8.1 Hz), 7.50(2H, d,J=8.4 Hz), 7.91(2H, d, J=8.4 Hz), 12.33(1H, s).

MS: 453.1(M+Na)⁺

Step 5

N-{4-{2-[4-(Hydroxymethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide(100 mg), N-hydroxyphthalimide (39.8 mg), triphenylphosphine (64 mg) andtetrahydrofuran (2 ml) were combined under nitrogen atmosphere, then,diethyl azodicarboxylate (40 wt % solution in toluene) (0.111 ml) wasadded to the solution at 0° C., and the mixture was stirred at 20° C.for 5 hrs. The reaction mixture was poured into saturated sodiumhydrogen carbonate aqueous solution, and extracted with chloroform. Theorganic layer was washed with brine, dried over magnesium sulfate,filtered and evaporated. The crude material was purified by preparativethin-layer chromatography over silica gel with chloroform/methanol(30:1) as an eluent to giveN-{4-[2-(4-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}phenyl)ethyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamideas a yellow foam.

¹H-NMR (CDCl₃), δ (ppm): 2.30(3H, S), 2.95–3.00(4H, m), 3.09(3H, s),5.15(2H, s), 7.04(2H, d, J=8.1 Hz), 7.21–7.92(10H, m), 9.31(!H, brs).

MS: 598.1(M+Na)⁺, 574.0(M−H)⁻

Step 6

To a solution ofN-{4-[2-(4-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}phenyl)ethyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide(116.8 mg) in N,N-dimethylformamide (1.1 ml) was added methylhydrazine(11.9 μl) under N₂ atmosphere, and the mixture was stirred at 20° C. for4 hrs. The reaction mixture was concentrated in vacuo. Ethyl acetate wasadded to the residue, and the precipitate was filtered off. The filtratewas concentrated in vacuo to give a crude yellow solid (105.1 mg). Thecrude material was purified by preparative thin-layer chromatographyover silica gel with chloroform/methanol (30:1) as an eluent to give apale yellow powder. The obtained powder was washed with acetonitrile,and the precipitate was collected by filtration to giveN-(4-(2-{4-[(aminooxy)methyl]phenyl}ethyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl)acetamide(8.4 mg) as a white solid.

¹H-NMR (DMSO-d₆), δ (ppm): 2.17(3H, s), 2.91–3.02(4H, m), 3.24(3H, s),4.51(2H, s), 5.98(2H, s), 7.09(2H, d, J=8.1 Hz), 7.19(2H, d, J=8.1 Hz),7.51(2H, d, J=8.4 Hz), 7.91(2H, d, J=8.1 Hz), 12.33(1H, brs).

MS: 468.0(M+H)⁺

PRODUCTION EXAMPLE 63 Synthesis ofN-{4-{2-[4-({[amino(imino)methyl]amino}methyl)phenyl]ethyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamidehydrochloride

Step 1

N-{4-{2-[4-(Bromomethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamidewas prepared fromN-(4-[2-{4-(hydroxymethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl)acetamidein a similar manner according to Step 9 of Production Example 61.

¹H-NMR (DMSO-d₆), δ (ppm): 2.17(3H, s), 2.90–3.10(4H, m), 3.23(3H, s),4.67(2H, s), 7.10(2H, d, J=8.1 Hz), 7.31(2H, d, J=8.1 Hz), 7.48(2H, d,J=8.4 Hz), 7.90(2H, d, J=8.4 Hz), 12.33(21H, s).

MS: 491.0(M−H)⁻

Step 2

To a solution ofN-{4-{2-[4-(bromomethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide(70 mg) in N,N-dimethylformamide (1 ml) was added diformimide sodiumsalt (13.5 mg), and the mixture was stirred for 10 min at 20° C. To thereaction mixture was added water, the mixture was extracted with ethylacetate, washed with water twice, dried over magnesium sulfate, andevaporated to give a crude diformimide compound. The diformimidecompound was suspended in conc. hydrocloric acid (200 μl), ethanol (2ml) and methanol (0.5 ml). The reaction mixture was stirred at 20° C.for 3 hrs., then at 50° C. for 3 hrs. The volatails were evaporated. Tothe residue was added saturated sodium hydrogen carbonate aqueoussolution, the mixture was extracted with chloroform, dried overmaganesium sulfate and evaporated to give crudeN-{4-(2-{4-[aminomethyl]phenyl}ethyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide,that was used as crude in the next reaction.

MS: 428.8(M+H)⁺

Step 3

Di-tert-butyl((E)-{[4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-4-yl}ethyl)benzyl]amino}methylidene)biscarbamatewas prepared in similar manner according to Step 3 of Production Example31.

¹H-NMR (CDCl₃), δ (ppm): 1.48(9H, s), 1.51(9H, s), 2.30(3H, s), 2.98(4H,s), 3.08(3H, s), 4.57(2H, d, J=5.1 Hz), 7.04(2H, d, J=8.1 Hz), 7.17(2H,d, J=8.1 Hz), 7.38(2H, d, J=8.4 Hz), 7.91(2H, d, J=8.4 Hz), 8.54(1H, t,J=5.1 Hz), 8.79(1H, s), 11.53(1H, s).

MS: 672.2(M+H)⁺

Step 4

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.18(3H, s), 2.90–3.05(4H, m), 3.25(3H, s),4.31(2H, d, J=6.2 Hz), 6.65–7.73(4H, brs), 7.14(2H, d, J=8.1 Hz),7.18(2H, d, J=8.1 Hz), 7.52(2H, d, J=8.4 Hz), 7.93(2H, d, J=8.4 Hz),12.35(1H, s).

MS: 506.0(M−H)⁻

PRODUCTION EXAMPLE 64 Synthesis of methyl4-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)benzoatehydrochloride

Step 1

Ethyl 4-(4-iodophenyl)-2-oxobutanoate was prepared from Ethyl3-(4-iodophenyl)propanoate in a similar manner according to Step 2 ofProduction Example 47.

¹H-NMR (CDCl₃), δ (ppm): 1.35(3H, t, J=7.0 Hz), 2.90(2H, t, J=7.5 Hz),3.15(2H, t, J=7.5 Hz), 4.31(2H, q, J=7.0 Hz), 6.96(2H, d, J=8.0 Hz),7.61(8.5 Hz).

MS: 331.0(M−H)⁻

Step 2

Ethyl 3-bromo-4-(4-iodophenyl)-2-oxobutanoate was prepared in a similarmanner according to Step 1 of Production Example 46.

¹H-NMR (CDCl₃), δ (ppm): 1.38(3H, t, J=7.0 Hz), 3.19(1H, dd, J=7.5, 14.6Hz), 3.47(1H, dd, J=7.5, 14.6 Hz), 4.36(2H, q, J=7.0 Hz), 5.21(1H, dd,J=7.5, 7.5 Hz), 7.00(2H, d, J=8.5 Hz), 7.65(2H, d, J=8.5 Hz).

MS: 369.2

Step 3

Ethyl 3-bromo-4-(4-iodophenyl)-2-oxobutanoate (1.32 g) was dissolved inethanol (26 ml), and then, thiourea (244 mg) was added to the solution.The reaction mixture was refluxed for 1 h under nitrogen atmosphere. Thecooled reaction mixture was evaporated in vacuo. The crude material wastriturated with diethyl ether to give ethyl2-amino-5-(4-iodobenzyl)-1,3-thiazole-4-carboxylate hydrobromide as apale yellow solid.

¹H-NMR (DMSO-d₆), δ (ppm): 1.27(3H, t, J=7.0 Hz), 4.28(2H, q, J=7.0 Hz),4.31(2H, s), 7.10(2H, d, J=8.5 Hz), 7.69(2H, d, J=8.5 Hz).

MS: 389.0(M+H)⁺, 411.0(M+Na)⁺

Step 4

Ethyl 2-amino-5-(4-iodobenzyl)-1,3-thiazole-4-carboxylate hydrobromide(1.386 g) was dissolved in dichloromethane (14 ml) under nitrogenatmosphere. Then, pyridine (0.765 ml) and acethyl chloride (0.336 ml)were added dropwise to the solution at 0° C. The reaction mixture wasstirred at 20° C. for 1 h. The organic solution was washed with1N-hydrochloric acid, water and brine, dried over magnesium sulfate, andconcentrated in vacuo. The residue was washed with diisopropyl ether togive ethyl 2-(acetylamino)-5-(4-iodobenzyl)-1,3-thiazole-4-carboxylateas a white solid.

¹H-NMR (DMSO-d₆), δ (ppm): 1.27(3H, t, J=7.0 Hz), 2.09(3H, s), 4.26(2H,q, J=7.0 Hz), 4.43(2H, s), 7.10(2H, d, J=8.0 Hz), 7.67(2H, d, J=8.0 Hz),12.44(1H, s).

MS: 431.0(M+H)⁺, 453.0(M+Na)⁺

Step 5

N-[4-Formyl-5-(4-iodobenzyl)-1,3-thiazol-2-yl]acetamide was prepared ina similar manner according to Step 4 of Production Example 46.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 4.48(2H, s), 7.11(2H, d, J=8.5Hz), 7.68(2H, d, J=8.5 Hz), 10.00(1H, s).

MS: 409.0(M+Na)⁺

Step 6

N-(5-(4-Iodobenzyl)-4-[2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl)acetamidewas prepared in a similar manner according to Step 5 of ProductionExample 45.

¹H-NMR (CDCl₃), δ (ppm): 2.07(3H×⅔, s), 2.15(3H×⅓, s), 3.96(2H×⅔, s),4.12(2H×⅓, s), 6.63(1H×⅔, d, J=12.6 Hz), 6.70(1H×⅔, d, J=12.6 Hz),6.94(2H×⅔, d, J=8.0 Hz), 6.99(2H×⅓, d, J=8.0 Hz), 7.12(1H×⅓, d, J=15.6Hz), 7.25(1H×⅓, d, J=15.6 Hz), 7.39(2H×⅔, d, J=9.0 Hz), 7.56(2H×⅓, d,J=8.5 Hz), 7.62(2H×⅔, d, J=8.0 Hz), 7.65(2H×⅓, d, J=8.5 Hz), 8.00(2H×⅔,d, J=8.5 Hz), 8.22(2H×⅓, d, J=8.5 Hz), 9.85(1H×⅓, s), 10.18(1H×⅔, s).

MS: 528.0(M+H)⁺

Step 7

To a solution of a mixture ofN-(5-(4-iodobenzyl)-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl)acetamideandN-{5-(4-iodobenzyl)-4-[(E)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide(Z:E=2:1) (558.2 mg) in methanol (2.8 ml) and N,N-dimethylformamide (5.5ml) were added palladium(II) acetate (49.6 mg),1,3-bis(diphenylphosphino)propane (109 mg) and triethylamine (308 μl).Carbon monooxide gas was bubbled through the solution for 30 min at 25°C. Then the reaction mixture was stirred for 6 hrs. at 70° C. undercarbon monooxide atmosphere. The reaction mixture was cooled to 25° C.,diluted with ethyl acetete, washed with brine, dried over magnesiumsulfate and evaporated to give a crude yellow foam (645 mg). The crudefoam was purified by flash column chromatography over silica gel withtoluene/ethyl acetate (2:1–3:2) as an eluent, and triturated with ethylether to give a mixture ofN-{5-(4-(methoxycarbonyl)benzyl)-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamideandN-{5-(4-(methoxycarbonyl)benzyl)-4-[(E)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide(Z:E=2:3) as a yellow solid.

¹H-NMR (CDCl₃), δ (ppm): 2.09(3H×⅖, s), 2.20(3H×⅗, s), 3.91(3H, s),4.10(2H×⅖, s), 4.25(2H×⅗, s), 7.27(2H×⅖, s), 7.14(1H×⅗, d, J=15.6 Hz),7.25(2H×⅖, d, J=9.0 Hz), 7.29(1H×⅗, d, J=15.6 Hz), 7.31(2H×⅗, d, J=8.5Hz), 7.38(2H×⅖, d, J=9.0 Hz), 7.57(2H×⅗, d, J=8.5 Hz), 7.97(2H×⅖, d,J=8.5 Hz), 7.99(2H×⅖, d, J=9.0 Hz), 8.00(2H×⅗, d, J=8.5 Hz), 8.20(2H×⅗,d, J=9.0 Hz), 9.55(1H×⅗, brs), 10.11(1H×⅖, brs).

MS: 460.1(M+Na)⁺

Step 8

Methyl4-({2-(acetylamino)-4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-5-yl}methyl)benzoatewas prepared in a similar manner according to Step 6 of ProductionExample 45.

¹H-NMR (CDCl₃), δ (ppm): 2.20(3H, s), 2.80(4H, s), 3.40–3.67(2H, m),3.83(2H, s), 3.90(3H, s), 6.57(2H, d, J=8.5 Hz), 6.84(2H, d, J=8.5 Hz),7.09(2H, d, J=8.0 Hz), 7.91(2H, d, J=8.5 Hz), 8.96(1H, brs).

MS: 410.2(M+H)⁺, 432.2(M+Na)⁺

Step 9

Methyl4-[(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)methyl]benzoatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

¹H-NMR (CDCl₃), δ (ppm): 1.49(9H, s), 1.54(9H, s), 2.20(2H, s), 2.83(4H,s), 3.88(2H, s), 3.89(3H, s), 7.03(2H, d, J=8.5 Hz), 7.17(2H, d, J=8.0Hz), 7.44(2H, d, J=8.0 Hz), 7.93(2H, d, J=8.5 Hz), 9.09(1H, brs),10.24(1H, s), 11.64(1H, s).

MS: 652.3(M+H)⁺, 652.3(M+Na)⁺

Step 10

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.86(4H, s), 3.83(3H, s),3.96–4.10(2H, m), 7.13(2H, d, J=8.5 Hz), 7.24(2H, d, J=9.0 Hz), 7.28(2H,d, J=8.5 Hz), 7.35(4H, s), 7.89(2H, d, J=8.0 Hz), 9.71(1H, 6), 12.01(1H,s).

MS: 452.2(M+H)⁻ free

PRODUCTION EXAMPLE 65 Synthesis of4-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)-N,N-dimethylbenzamidehydrochloride

Step 1

Methyl4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]methyl}benzoatewas prepared from the compound obtained in Step 8 of Production Example64 in a similar manner according to Step 1 of Production Example 52.

¹H-NMR (CDCl₃), δ (ppm): 1.52(9H, s), 2.23(3H, s), 2.81(4H, s), 3.86(2H,s), 3.90(3H, s), 6.93(2H, d, J=8.0 Hz), 7.13(2H, d, J=8.5 Hz), 7.19(2H,d, J=8.0 Hz), 7.91(2H, d, J=8.5 Hz), 8.48–9.69(1H, brs).

MS: 510.2(M+H)⁺, 532.3(M+Na)⁺

Step 2

Methyl4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]methyl}benzoate(287.7 mg), 1N-sodium hydroxide (1.41 ml) and ethanol (2.9 ml) werecombined, and the mixture was refluxed for 3 hrs. After cooling to 25°C., the organic solvent was removed in vacuo. The aqueous solution wasacidified with 1N-hydrochloric acid (pH=4), and the precipitate wasfiltered in vacuo to give 312.5 mg of a pale yellow solid. The solid wasdissolved in pyridine (4.3 ml) under nitrogen atmosphere, and then,acethyl chloride (0.12 ml) was added dropwise to the solution at 0° C.The reaction mixture was stirred at 25° C. for 3 hrs., and pyridine wasremoved in vacuo. The residue was suspended in water, and acidified with1N-hydrochloric acid. The precipitate was collected in vacuo. The solidwas washed with water and diethyl ether to give4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]methyl}benzoicacid as a pale yallow solid.

¹H-NMR (DMSO-d₆), δ (ppm): 1.47(9H, s), 2.08(3H, s), 2.70–2.90(4H, m),3.92(2H, s), 6.99(2H, d, J=8.4 Hz), 7.10(2H, d, J=8.0 Hz), 7.33(2H, d,J=8.0 Hz), 7.81(2H, d, J=8.4 Hz), 9.24(1H, s), 12.00(1H, s), 12.84(1H,brs).

MS: 494.4(M−H)⁻

Step 3

To a solution of4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,13-thiazol-5-yl]methyl}benzoicacid (50 mg) in 0.5 ml of dichloromethane were added methylaminehydrochloride (10.7 mg), 1-hydroxybenzotriazole (20.4 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (55.3 μl), then, themixture was stirred for 3 hrs. at 25° C. The reaction mixture wasdiluted with 10 ml of chloroform and washed with water and brine. Theorganic layer was dried over magnesium sulfate and evaporated undervaccum. The residue was triturated with ethyl acetate anddiisopropylether, and collected by filtration to give tert-butyl{4-[2-(2-(acetylamino)-5-{4-[(dimethylamino)carbonyl]benzyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamateas a pale yellow solid.

¹H-NMR (CDCl₃), δ (ppm): 1.51(9H, s), 2.23(3H, s), 2.83(4H, s), 2.95(3H,s), 3.09(3H, s), 3.82(2H, s), 6.47–6.81(1H, brs), 6.94(2H, d, J=8.1 Hz),7.05(2H, d, J=8.1 Hz), 7.18(2H, d, J=8.1 Hz), 7.28(2H, d, J=8.1 Hz),8.50–9.09(1H, brs).

MS: 523.3(M+H)⁺, 545.2(M+Na)⁺

Step 4

tert-Butyl{4-[2-(2-(acetylamino)-5-{4-[(dimethylamino)carbonyl]benzyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamate(39.1 mg) and trifluoroacetic acid (1 ml) were combined at 0° C. Thereaction mixture was stirred at 25° C. for 2 hrs., and concentrated invacuo. The residue was added to chloroform (20 ml) and 1N-sodiumhydroxide (10 ml). The oraganic layer was separated, dried withmagnesium sulfate, and evaporated to give yellow oil (33.3 mg). Thecrude yellow oil,N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (45.8 mg) andtetrahydrofuran (0.5 ml) were combined under nitrogen atmosphere, andthe mixture was stirred at 25° C. for 34 hrs. To the reaction mixturewas added N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (11mg), and the mixture was stirred at 50° C. for 3 hrs. Then, the mixturewas concentrated in vacuo. The residue was purified by preparativethin-layer chromatography over silica gel with chloroform/methanol(20:1) as an eluent to give di-tert-butyl[(E)-({4-[2-(2-(acetylamino)-5-{4-[(dimethylamino)carbonyl]benzyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamateas colorless oil (12.9 mg).

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.54(9H, s), 2.21(3H, s), 2.85(4H,s), 2.96(3H, brs), 3.08(3H, brs), 3.86(2H, s), 7.06(2H, d, J=8.5 Hz),7.14(2H, d, J=8.1 Hz), 7.33(2H, d, J=8.5 Hz), 7.46(2H, d, J=8.5 Hz),8.81–9.21(1H, brs), 10.25(1H, s), 11.63(1H, s).

MS: 665.3(M+H)⁺, 687.2(M+Na)⁺

Step 5

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.86(4H, s), 2.88(3H, s),2.96(3H, s), 3.97(2H, s), 7.12(2H, d, J=8.4 Hz), 7.16(2H, d, J=8.1 Hz),7.23(2H, d, J=8.4 Hz), 7.32(2H, d, J=8.1 Hz), 7.34(4H, s), 9.70(1H, s),12.01(1H, s).

MS: 465.2(M+H)⁺ free

PRODUCTION EXAMPLE 66 Synthesis of4-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)-N-methylbenzamidehydrochloride

Step 1

tert-Butyl{4-[2-(2-(acetylamino)-5-{4-[(methylamino)carbonyl]benzyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamatewas prepared from the compound obtained in Step 2 of Production Example65 in a similar manner according to Step 3 of Production Example 65.

¹H-NMR (CDCl₃), δ (ppm): 1.52(9H, s), 2.23(3H, s), 2.78–2.89(4H, m),3.00(3H, d, J=4.8 Hz), 3.83(2H, s), 6.20(2H, d, J=4.8 Hz), 6.36–6.78(1H,brs), 6.94(2H, d, J=8.4 Hz), 7.05(2H, d, J=8.4 Hz), 7.18(2H, d, J=8.4Hz), 7.63(2H, d, J=8.4 Hz), 8.60–9.09(1H, brs).

MS: 509.2(M+H)⁺, 531.2(M+Na)⁺

Step 2

Di-tert-butyl[(E)-({4-[2-(2-(acetylamino)-5-{4-[(methylamino)carbonyl]benzyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared in a similar manner according to Step 4 of ProductionExample 65.

¹H-NMR (CDCl₃), δ (ppm): 1.49(9H, s), 1.54(9H, s), 2.22(3H, s), 2.83(4H,s), 2.99(3H, d, J=4.8 Hz), 3.86(2H, s), 6.16(1H, d, J=4.0 Hz), 7.01(2H,d, J=8.4 Hz), 7.13(2H, d, J=8.4 Hz), 7.42(2H, d, J=8.4 Hz), 7.66(2H, d,J=8.4 Hz), 8.77–9.10(1H, brs), 10.24(1H, s), 11.62(1H, s).

MS: 651.3(M+H)⁺, 673.3(M+Na)⁺

Step 3

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.08(3H, s), 2.76(3H, d, J=4.8 Hz), 2.86(4H,s), 3.98(2H, s), 7.13(2H, d, J=8.4 Hz), 7.19(2H, d, J=8.1 Hz), 7.23(2H,d, J=8.4 Hz), 7.30(4H, s), 7.74(2H, d, J=8.1 Hz), 8.38(2H, d, J=4.4 Hz),9.62(1H, s), 11.99(1H, s).

MS: 451.3(M+H)⁻ free

PRODUCTION EXAMPLE 67 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[(dimethylamino)methyl]-1,3-thiazol-2-yl}acetamidedihydrochloride

Step 1

To a solution ofN-{4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide (500 mg) inacetic acid (3 ml) were added dimethylamine hydrochloride (169 mg) andparaformaldehyde (62.2 mg), and the mixture was stirred at 100° C. (bathtemp.) for 2 hrs. The solvent was removed in vacuo, and the mixture wasadjusted to pH=9 with saturated sodium hydrogen carbonate aqueoussolution, extracted with ethyl acetate. The organic layer was washedwith brine, dried over magnesium sulfate and evaporated. The crudecompound was purified by flash column chromatography over silica gelwith dichloromethane/methanol (100:1)→(20:1) as an eluent to giveN-{5-[(dimethylamino)methyl]-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamideas a yellow amorphous substance.

¹H-NMR (CDCl₃), δ (ppm): 2.08(3H, s), 2.26(6H, s), 3.47(2H, s), 6.63(1H,d, J=12.6 Hz), 6.70(1H, d, J=12.6 Hz), 7.43(2H, d, J=9.0 Hz), 8.03(2H,d, J=9.0 Hz), 10.20(1H, brs).

MS: 347(M+H)⁺, 369(M+Na)⁺

Step 2

N-{4-[2-(4-Aminophenyl)ethyl]-5-[(dimethylamino)methyl]-1,3-thiazol-2-yl}acetamidewas prepared in a similar manner according to Step 6 of ProductionExample 45.

¹H-NMR (CDCl₃), δ (ppm): 2.19(6H, s), 2.23(3H, s), 2.80(4H, s), 3.30(2H,s), 3.56(2H, s), 6.60(2H, d, J=8.4 Hz), 6.91(2H, d, J=8.4 Hz),8.54–8.84(1H, brs).

MS: 317.2(M−H)⁻

Step 3

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[(dimethylamino)methyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared in a similar manner according to Step 7 of ProductionExample 45.

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.53(9H, s), 2.21(6H, s), 2.22(3H,s), 2.87(4H, s), 3.36(2H, s), 7.09(2H, d, J=8.5 Hz), 7.46(2H, d, J=8.5Hz), 8.89–9.97(1H, brs), 10.24(1H, s), 11.63(1H, s).

MS: 561.3(M+H)⁺, 583.3(M+Na)⁺

Step 4

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 2.66(3H, s), 2.68(3H, s),2.96(4H, s), 4.37(2H, d, J=4.8 Hz), 7.15(2H, d, J=8.4 Hz), 7.32(2H, d,J=8.4 Hz), 7.51(4H, s), 10.08(1H, s), 10.64(1H, t, J=4.8 Hz), 12.33(1H,s).

MS: 361.1(M+H)⁺

PRODUCTION EXAMPLE 68 Synthesis ofN-{5-[(4-acetyl-1-piperazinyl)methyl]-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamidedihydrochloride

Step 1

N-{5-[(4-Acetyl-1-piperazinyl)methyl]-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamidewas prepared fromN-{4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide in asimilar manner according to Step 1 of Production Example 67.

¹H-NMR (CDCl₃), δ (ppm): 2.08(6H, s), 2.34–2.59(4H, m), 3.41–3.53(2H,m), 3.56(2H, s), 3.58–3.69(2H, m), 6.62(1H, d, J=12.6 Hz), 6.68(1H, d,J=12.6 Hz), 7.45(2H, d, J=8.5 Hz), 8.05(2H, d, J=9.0 Hz), 10.18(1H, s).

MS: 452.0(M+Na)⁺

Step 2

N-(5-[(4-Acetyl-1-piperazinyl)methyl]-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl)acetamide(1080 mg), methanol (2 ml), tetrahydrofuran (2 ml), acetic acid (0.3 ml)and then 10% palladium on carbon (150 mg) were combined under nitrogenatmosphere. The mixture was stirred under 3 atm hydrogen for 3 hrs. at25° C. The reaction mixture was filtered through a celite pad, and thefiltrate was concentrated in vacuo to give a crude material (192.3 mg).To the residue was added saturated sodium hydrogen carbonate aqueoussolution, and the mixture was extracted with chroloform. The organiclayer was washed with brine, dried over MgSO₄, and concentrated in vacuoto give a pink amorphous substance (124.7 mg). The pink amorphoussubstance (124.7 mg),N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (93.6 mg) andtetrahydrofuran (2 ml) were combined under nitrogen atmosphere. Thereaction mixture was stirred at 25° C. for 14 hrs., and concentrated invacuo. The residue was purified by preparative thin-layer chromatographyover silica gel with chloroform/methanol (20:1) as an eluent to givedi-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[(4-acetyl-1-piperazinyl)methyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamateas colorless oil (121.1 mg).

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.53(9H, s), 2.06(3H, s), 2.24(3H,s), 2.20–2.32(2H, m), 2.33–2.44(2H, m), 2.74–2.96(4H, m), 3.30–3.45(4H,m), 3.52–3.65(2H, m), 7.04(2H, d, J=8.5 Hz), 7.45(2H, d, J=8.5 Hz),8.85–10.17(1H, brs), 10.25(1H, s), 11.63(1H, s).

MS: 644.3(M+H)⁺, 666.1(M+H)⁺

Step 3

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.03(3H, s), 2.16(3H, s), 2.75–3.15(8H, m),3.16–3.63(4H, m), 4.40(2H, s), 7.15(2H, d, J=8.0 Hz), 7.32(2H, d, J=8.0Hz), 7.49(4H, s), 10.07(1H, s), 11.29(1H, brs), 12.33(1H, s)

MS: 444.2(M+H)⁺ free

PRODUCTION EXAMPLE 69 Synthesis ofN-(4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-{[4-(methylsulfonyl)-1-piperazinyl]methyl}-1,3-thiazol-2-yl)acetamidedihydrochloride

Step 1

N-{5-{[4-(Methylsulfonyl)-1-piperazinyl]methyl}-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamidewas prepared fromN-{4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide in asimilar manner according to Step 1 of Production Example 67.

¹H-NMR (CDCl₃), δ (ppm): 2.08(3H, s), 2.54–2.66(4H, m), 2.80(3H, s),3.19–3.34(4H, m), 3.58(2H, s), 6.61(1H, d, J=12.1 Hz), 6.69(1H, d,J=12.1 Hz), 7.45(2H, d, J=8.5 Hz), 8.04(2H, d, J=8.5 Hz), 10.09(1H, s).

MS: 467.2(M+H)⁺, 488.1(M+Na)⁺

Step 2

Di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{[4-(methylsulfonyl)-1-piperazinyl]methyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared in a similar manner according to Step 2 of ProductionExample 68.

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.54(9H, s), 2.23(3H, s),2.41–2.56(4H, m), 2.76(3H, s), 2.80–2.89(4H, m), 3.12–3.27(4H, m),3.42(2H, s), 7.05(2H, d, J=8.5 Hz), 7.45(2H, d, J=8.5 Hz), 8.57–9.61(1H,brs), 10.25(1H, s), 11.63(1H, s).

MS: 680.3(M+H)⁻, 702.2(M+Na)⁻

Step 3

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 2.97(4H, s), 3.00(3H, s),3.05–3.28(4H, m), 3.28–3.48(2H, m), 3.59–3.81(2H, m), 4.35–4.60(2H,brs), 7.16(2H, d, J=8.1 Hz), 7.32(2H, d, J=8.1 Hz), 7.39(4H, s),9.84(1H, s), 10.64–10.89(1H, brs), 12.34(1H, s).

MS: 480.1(M+H)⁻ free

PRODUCTION EXAMPLE 70 Synthesis ofN-[4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-(4-thiomorpholinylmethyl)-1,3-thiazol-2-yl]acetamidedihydrochloride

Step 1

N-[4-[(Z)-2-(4-Nitrophenyl)vinyl]-5-(4-thiomorpholinylmethyl)-1,3-thiazol-2-yl]acetamidewas prepared fromN-{4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide in asimilar manner according to Step 1 of Production Example 67.

¹H-NMR (CDCl₃), δ (ppm): 2.08(3H, s), 2.57–2.86(8H, m), 3.53(2H, s),6.62(1H, d, J=12.6 Hz), 6.68(1H, d, J=12.6 Hz), 7.43(2H, d, J=9.0 Hz),8.0332(2H, d, J=9.0 Hz), 10.16(1H, s).

MS: 405.1(M+H)⁺, 427.1(M+Na)⁺

Step 2

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-(4-thiomorpholinylmethyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in a similar manner according to Step 2 of ProductionExample 68.

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.53(9H, s), 2.22(3H, s), 2.63(8H,s), 2.80–2.90(4H, m), 3.39(2H, s), 7.06(2H, d, J=8.5 Hz), 7.45(2H, d,J=8.5 Hz), 8.82–9.39(1H, brs), 10.24(1H, s), 11.63(1H, s).

MS: 619.3(M+H)⁺, 641.2(M+Na)⁺

Step 3

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 2.69–2.87(2H, m), 2.97(4H, s),3.02–3.19(4H, m), 3.48–3.61(2H, m), 4.42(2H, s), 7.15(2H, d, J=8.4 Hz),7.31(2H, d, J=8.4 Hz), 7.40(4H, s), 9.86(1H., s), 10.51–10.69(1H, brs),12.34(1H, s).

MS: 419.2(M+H)⁻ free

PRODUCTION EXAMPLE 71 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[2-(dimethylamino)-2-oxoethyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

tert-Butyl(4-{2-[2-(acetylamino)-5-({[2-(dimethylamino)-2-oxoethyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamatewas prepared from2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylicacid in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.46(9H, s), 2.15(3H, s), 2.72,2.85(3H, s), 2.89, 2.98(3H, s), 3.16(4H, m), 4.01(2H, m), 7.07(2H, d,J=8.2 Hz), 7.32(2H, d, J=8.2 Hz), 7.87–7.95(1H, m), 9.21(1H, s),12.36(1H, s).

MS: 490(M+H)⁺

Step 2

2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-N-[2-(dimethylamino)-2-oxoethyl]-1,3-thiazole-5-carboxamidehydrochloride was prepared in a similar manner according to Step 2 ofProduction Example 31.

white powder

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.16(3H, s), 2.85(3H, s),2.86–2.98(5H, m), 3.22(2H, dd, J=8.9, 5.3 Hz), 4.01(2H, d, J=5.3 Hz),7.27(2H, d, J=8.5 Hz), 7.33(2H, d, J=8.5 Hz), 7.94(1H, t, J=5.3 Hz),10.15(2H, br), 12.38(1H, s).

MS: 390(M+H)⁺ free

Step 3

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[2-(dimethylamino)-2-oxoethyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

white powder

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.15(3H,s), 2.85(3H, s), 2.85–2.94(2H, m), 2.97(3H, s), 3.17–3.26(2H, m),4.00–4.04(2H, m), 7.19(1H, d, J=8.0 Hz), 7.42(2H, d, J=8.0 Hz), 7.88(1H,t, J=5.4 Hz), 9.93(1H, s), 11.43(1H, s), 12.38 (1H, s).

MS: 632(M+H)⁺

Step 4

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

white powder

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.16(3H, s), 2.84(3H, s),2.89–2.695(2H, m), 2.98(3H, s), 3.19–3.26(2H, m), 3.99(2H, m), 7.13(2H,d, J=8.0 Hz), 7.28(2H, d, J=8.0 Hz), 7.43(4H, br), 7.97(1H, br),9.86(1H, s), 12.38(1H, s).

MS: 432(M+H)⁺ free

PRODUCTION EXAMPLE 72 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[3-(dimethylamino)-3-oxopropyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

tert-Butyl(4-{2-[2-(acetylamino)-5-({[3-(dimethylamino)-3-oxopropyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamatewas prepared from2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylicacid in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.46(9H, s), 2.14(3H, s), 2.55(2H,m), 2.73–2.94(8H, m), 3.14(2H, dd, J=9.1, 6.1 Hz), 3.37(2H, m), 7.05(2H,d, J=8.5 Hz), 7.32(2H, d, J=8.5 Hz), 7.89(1H, m), 9.21(1H, s), 12.33(1H,s).

MS: 504(M+H)⁺

Step 2

2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-N-[3-(dimethylamino)-3-oxopropyl]-1,3-thiazole-5-carboxamidehydrochloride was prepared in a similar manner according to Step 2 ofProduction Example 31.

white powder

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.15(3H, s), 2.57(2H, m), 2.81(3H,s), 2.84–2.98(5H, m), 3.20(2H, dd, J=8.9, 5.4 Hz), 3.36(2H, dd, J=12.8,7.1 Hz), 7.26(2H, d, J=8.6 Hz), 7.32(2H, d, J=8.6 Hz), 7.95(1H, t, J=5.4Hz), 10.04(2H, br), 12.35(1H, br).

MS: 403(M+H)⁺ free

Step 3

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[3-(dimethylamino)-3-oxopropyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

white powder

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39(9H, s), 1.50(9H, s), 2.14(3H,s), 2.80(3H, s), 2.81–2.93(2H, m), 2.94(3H, s), 3.13–3.29(6H, m),3.34–3.43(2H, m), 7.17(2H, d), 7.42(2H, d), 7.89(1H, m), 9.93(1H, s),11.43(1H, s), 12.34(1H, m).

MS: 646(M+H)⁺

Step 4

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

white powder

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.16(3H, s), 2.56(2H, m), 2.81(3H,s), 2.87–2.95(5H, m), 3.19(2H, m), 3.34(2H, m), 7.11–7.38(4H, m),7.43(4H, s), 8.02(1H, m), 8.55(1H, br), 9.88(1H, br), 12.36(1H, s).

MS: 445(M+H)⁺ free

PRODUCTION EXAMPLE 73 Synthesis of2-(acetylamino)-N-[2-(acetylamino)ethyl]-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

tert-Butyl(4-{2-[2-(acetylamino)-5-({[2-(acetylamino)ethyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamatewas prepared from2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylicacid in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.46(9H, s), 1.79(3H, s), 2.14(3H,s), 2.84(2H, m), 3.16–3.22(6H, m), 7.06(2H, d, J=8.5 Hz), 7.33(2H, d,J=8.5 Hz), 7.99(2H, m), 9.21(1H, s), 12.33(1H, s).

MS: 490(M+H)⁺

Step 2

2-(Acetylamino)-N-[2-(acetylamino)ethyl]-4-[2-(4-aminophenyl)ethyl]-1,3-thiazole-5-carboxamidehydrochloride was prepared in a similar manner according to Step 2 ofProduction Example 31.

white powder

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.79(3H, s), 2.15(3H, s),2.90–2.98(2H, dd, J=10.1, 6.6 Hz), 3.14–3.26(6H, m), 7.27(2H, d, J=8.9Hz), 7.32(2H, d, J=8.9 Hz), 7.97–8.06(2H, m), 10.18(2H, br), 12.35(1H,s).

MS: 390(M+H)⁺ free

Step 3

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[2-(acetylamino)ethyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

white powder

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 1.79(3H,s), 2.15(3H, s), 2.89(2H, m), 3.18(6H, m), 7.18(2H, d, J=8.0 Hz),7.42(2H, d, J=8.0 Hz), 7.95(2H, m), 9.93(1H, s), 11.43(1H, s), 12.35(1H,s).

MS: 632(M+H)⁺

Step 4

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

white powder

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.79(9H, s), 2.16(9H, s), 2.91(2H,m), 3.10–3.25(6H, m), 7.14(2H, d, J=8.2 Hz), 7.27(2H, d, J=8.2 Hz),7.42(4H, br), 7.97(1H, br), 8.08(1H, br), 9.83(1H, s), 12.36(1H, s).

MS: 432(M+H)⁺ free

PRODUCTION EXAMPLE 74 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-{2-[(methylsulfonyl)amino]ethyl}-1,3-thiazole-5-carboxamidehydrochloride

Step 1

tert-Butyl[4-(2-{2-(acetylamino)-5-[({2-[(methylsulfonyl)amino]ethyl}amino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamatewas prepared from2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylicacid in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.46(9H, s), 2.15(3H, s),2.79–2.89(5H, m), 3.05–3.32(6H, m), 7.04–7.14(3H, m), 7.33(2H, d, J=8.3Hz), 8.01(1H, br), 9.20(1H, s), 12.35(1H, s).

MS: 526(M+H)⁺

Step 2

2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-N-{2-[(methylsulfonyl)amino]ethyl}-1,3-thiazole-5-carboxamidehydrochloride was prepared in a similar manner according to Step 2 ofProduction Example 31.

white powder

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.15(3H, s), 2.89(3H, s),2.89–3.27(8H, m), 7.12(1H, t, J=5.7 Hz), 7.24(2H, d, J=8.5 Hz), 7.32(2H,d, J=8.5 Hz), 8.05(1H, t, J=5.4 Hz), 9.95(2H, br), 12.36(1H, s).

MS: 425(M+H)⁺ free

Step 3

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[({2-[(methylsulfonyl)amino]ethyl}amino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

white powder

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.15(3H,s), 2.80–2.97(5H, m), 3.00–3.14(2H, m), 3.15–3.30(4H, 15 m), 7.11(1H,m), 7.17(2H, d, J=8.5 Hz), 7.42(2H, d, J=8.5 Hz), 8.01(1H, m), 9.93(1H,s), 11.43(1H, s), 12.37(1H, s).

MS: 668(M+H)⁺

Step 4

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

white powder

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.16(3H, s), 2.90–2.96(5H, m),3.08(2H, m), 3.19–3.29(4H, q), 7.14(2H, d, J=8.3 Hz), 7.28(2H, d, J=8.3Hz), 7.43(4H, br), 8.07(1H, m), 9.87(1H, s), 12.38(1H, s).

MS: 467(M+H)⁺ free

PRODUCTION EXAMPLE 75 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[3-(dimethylamino)-3-oxopropyl]-N-methyl-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{[[3-(dimethylamino)-3-oxopropyl](methyl)amino]carbonyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39(9H, s), 1.50(9H, s), 2.14(3H,s), 2.56(2H, t, J=7.3 Hz), 2.78(3H, s), 2.84–2.88(6H, m), 2.93(3H, s),3.47(3H, m), 7.12(2H, d, J=8.4 Hz), 7.40(2H, d, J=8.4 Hz), 9.92(1H, s),11.43(1H, s), 12.34(1H, s).

MS: 659(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.15(3H, s), 2.50–2.60(6H, m),2.79(3H, s), 2.87(3H, s), 2.94(3H, s), 3.39–3.64(2H, m), 7.09–7.26(4H,m), 7.46(4H, br), 9.96(1H, s), 12.35(1H, s).

MS: 460(M+H)⁺ free

PRODUCTION EXAMPLE 76 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-{3-[benzyl(methyl)amino]-3-oxopropyl}-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[({3-[benzyl(methyl)amino]-3-oxopropyl}amino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.83(9H, s), 1.50(9H, s),1.98–2.15(3H, m), 2.60–2.63(2H, m), 2.80–2.90(5H, m), 3.17–3.21(2H, m),3.42–3.47(2H, m), 4.50–4.57(2H, m), 7.12–7.43(9H, 30 m), 7.95(1H, m),9.93(1H, s), 11.44(1H, s), 12.4(1H, s).

MS: 722(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.16, 2.30(3H, s), 2.64(2H, m),2.64(2H, m), 2.80–2.90(5H, m), 3.14–3.25(2H, m), 3.43–3.47(2H, m),4.51–4.57(2H, m), 7.08–7.42(9H, m), 8.02–8.04(1H, m), 9.83–9.87(1H, m),12.36(1H, m).

MS: 522(M+H)⁺ free

PRODUCTION EXAMPLE 77 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[4-(dimethylamino)-4-oxobutyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[4-(dimethylamino)-4-oxobutyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39(9H, s), 1.50(9H, s), 1.68(2H,tt, J=6.8 Hz), 2.14(3H, s), 2.30(2H, t, J=6.8 Hz), 2.80(3H, s),2.82–2.95(2H, m), 2.92(3H, s), 3.10–3.28(4H, m), 7.18(2H, d, J=8.5 Hz),7.39(2H, d, J=8.5 Hz), 9.92(1H, s), 11.43(1H, br), 12.3(1H, br).

MS: 682(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.69(2H, m), 2.16(2H, s), 2.31(2H,t, J=7.2 Hz), 2.81(3H, s), 2.87–2.95(2H, m), 2.93(3H, s), 3.16–3.24(4H,m), 3.57(3H, s), 7.11–7.44(4H, m), 8.06–8.23(1H, m), 9.83–9.92(1H, m),12.35(1H, s).

MS: 460(M+H)⁺ free

PRODUCTION EXAMPLE 78 Synthesis of(2R)-1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}carbonyl)-N,N-dimethyl-2-pyrrolidinecarboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({(2R)-2-[(dimethylamino)carbonyl]-1-pyrrolidinyl}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39(9H, s), 1.50(9H, s),1.60–1.93(3H, m), 2.06–2.30(1H, m), 2.14(3H, s), 2.66–3.14(10H, m),3.20–3.50(2H, m), 4.89(1H, m), 7.16(2H, d, J=8.0 Hz), 7.41(2H, d, J=8.0Hz), 9.92(1H, s), 11.41(1H, s), 12.34(1H, s).

MS: 694(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.60–2.00(3H, m), 2.15, 2.48(3H, s×2), 2.65–3.50(12H, m), 3.60–3.75(2H, m), 7.09–7.17(2H, d ×2),7.23–7.31(2H, d ×2), 7.47(3H, br), 9.94(1H, br), 12.35, 12.59(1H, s ×2).

MS: 472(M+H)⁺ free

PRODUCTION EXAMPLE 79 Synthesis of(2S)-1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}carbonyl)-N,N-dimethyl-2-pyrrolidinecarboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({(2S)-2-[(dimethylamino)carbonyl]-1-pyrrolidinyl}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39(3H, s), 1.50(9H, s),1.60–1.94(H, m), 2.14(3H, s), 2.10–2.36(1H, m), 2.67–3.11(10H, m),3.30–3.52(2H, m), 4.88(1H, m), 7.16(2H, d, J=8.0 Hz), 7.41(2H, d, J=8.0Hz), 9.92(1H, s), 11.41(1H, s), 12.34(1H, 5 s).

MS: 694(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.60–2.00(3H, m), 2.15, 2.48(3H, s×2), 2.65–3.50(12H, m), 3.60–3.75(2H, m), 7.09–7.17(2H, d ×2),7.23–7.31(2H, d ×2), 7.47(3H, br), 9.94(1H, br), 12.35, 12.59(1H, s ×2).

MS: 472(M+H)⁺ free

PRODUCTION EXAMPLE 80 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[2-(methylsulfonyl)ethyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[2-(methylsulfonyl)ethyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz; DMSO-d₆), δ (ppm): 1.39(9H, s), 1.57(9H, s), 2.15(3H,s), 2.87(2H, dd, J=8.8, 6.5 Hz), 3.02(3H, s), 3.19–3.28(2H, dd, J=9.0,5.5 Hz), 3.30–3.36(2H, m), 3.59(2H, dd, J=12.0, 6.0 Hz), 7.17(2H, d,J=8.4 Hz), 7.42(2H, d, J=8.4 Hz), 8.17(1H, s), 9.93(1H, s), 11.44(1H,s), 12.40(1H, s).

MS: 675(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.16(3H, s), 2.88–2.96(2H, m),3.03(3H, s), 3.20–3.30(4H, m), 3.33–3.60(2H, m), 7.12–7.18(2H, m),7.26–7.46(2H, d), 7.46(4H, br), 8.27(1H, t), 9.94(1H, s), 12.41(1H, s).

MS: 453(M+H)⁺ free

PRODUCTION EXAMPLE 81 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-(4-pyridinylmethyl)-1,3-thiazole-5-carboxamidedihydrochloride

Step 1

Di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{[(4-pyridinylmethyl)amino]carbonyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.40–1.50(18H, br), 2.15(3H, s),2.89(2H, m), 3.22(2H, m), 4.39(2H, d, J=5.7 Hz), 7.09–7.18(2H, m),7.32–7.44(3H, m), 7.66(1H, m), 8.43–8.62(3H, m), 9.94(1H, s), 11.44(1H,s), 12.40(1H, s).

MS: 660(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.18(3H, s), 2.92(2H, m),3.13–3.28(2H, m), 4.63(2H, m), 7.12(2H, d, J=8.4 Hz), 7.24(2H, d, J=8.4Hz), 7.47(4H, br), 7.93(2H, d, J=6.3 Hz), 8.88(3H, m), 10.00(1H, s),12.43(1H, s).

MS: 438(M+H)⁺ free

PRODUCTION EXAMPLE 82 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-(3-pyridinylmethyl)-1,3-thiazole-5-carboxamidedihydrochloride

Step 1

Di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{[(3-pyridinylmethyl)amino]carbonyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39(9H, s), 1.50(9H, s), 2.16(3H,s), 2.89(2H, dd, J=8.6, 6.7 Hz), 3.22(2H, dd, J=8.6, 5.7 Hz), 4.38(2H,d, J=5.7 Hz), 7.13(2H, d, J=8.4 Hz), 7.25(2H, s ×2, J=5.7 Hz), 7.41(2H,d, J=8.4 Hz), 8.50(2H, s ×2, J=5.0 Hz), 8.62(1H, dd, J=5.0, 5.7 Hz),9.93(1H, s), 11.43 (1H, s), 12.41(1H, s).

MS: 660(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.17(3H, s), 2.92(2H, m), 3.23(2H,m), 4.56(2H, m), 7.10–7.31(4H, m), 7.45(4H, br), 8.01(1H, dd, J=8.1, 5.9Hz), 8.82(1H, d, J=8.0 Hz), 8.84(2H, s), 8.96(1H, s), 12.45(1H, s).

MS: 438(M+H)⁺ free

PRODUCTION EXAMPLE 83 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-{2-[(2-phenylacetyl)amino]ethyl}-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[({2-[(2-phenylacetyl)amino]ethyl}amino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.15(3H,s), 2.88(2H, m), 3.25–3.31(6H, m), 3.38(2H, s), 7.15–7.44(7H, m),7.32(2H, d, J=8.3 Hz), 7.98(1H, br), 8.11(1H, br), 9.93(1H, s),11.43(1H, s), 12.35(1H, s).

MS: 730(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.16(3H, s), 2.90(2H, br), 3.20(6H,m), 7.11–7.31(9H, m), 7.38(3H, s), 8.06–8.16(2H, m), 9.75(1H, s),12.33(1H, s).

MS: 508(M+H)⁺ free

PRODUCTION EXAMPLE 84 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[5-(dimethylamino)-5-oxopentyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[5-(dimethylamino)-5-oxopentyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39(9H, s), 1.39–1.50(4H, m),1.57(9H, s), 2.14(3H, s), 2.29(2H, br), 2.79(3H, s), 2.84–2.94(2H, m),2.94(3H, s), 3.15–3.23(4H, m), 7.16(2H, d, J=8.3 Hz), 7.42(2H, d, J=8.3Hz), 7.97(1H, br), 9.93(1H, s), 11.44(1H, s), 12.35(1H, s).

MS: 696(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39–1.56(4H, m), 2.16(2H, m),2.29(3H, s), 2.83–2.98(5H, m), 3.06–3.28(4H, m), 7.13(2H, d, J=8.5 Hz),7.25(2H, d, J=8.5 Hz), 7.40(3H, br), 8.06(1H, br), 9.79(1H, s).

MS: 474(M+H)⁺ free

PRODUCTION EXAMPLE 85 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[3-(benzylamino)-3-oxopropyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[3-(benzylamino)-3-oxopropyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39(9H, s), 1.50(9H, s), 2.15(3H,s), 2.45(2H, t, J=7.2 Hz), 2.73(2H, m), 3.20(2H, m), 3.39(2H, m),4.26(2H, d, J=5.8 Hz), 7.15–7.28(7H, m), 7.41(2H, d, J=8.4 Hz), 8.02(1H,t, J=5.5 Hz), 8.40(1H, t, J=5.5 Hz), 9.93(1H, s), 11.4(1H, br), 12.3(1H,br).

MS: 730(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.16(3H, s), 2.41(2H, t, J=7.0 Hz),2.90(2H, m), 3.20(2H, m), 3.39(2H, m), 3.63(2H, m), 4.27(2H, d, J=5.8Hz), 7.11–7.37(9H, m), 7.37(4H, s), 8.09(1H, t, J=5.5 Hz), 8.43(1H, t,J=6.0 Hz), 9.74(1H, s), 12.35(1H, s).

MS: 508(M+H)⁺ free

PRODUCTION EXAMPLE 86 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[6-(dimethylamino)-6-oxohexyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[6-(dimethylamino)-6-oxohexyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.13–1.50(24H, m), 2.14(3H, s),2.24(2H, t, J=8.0 Hz), 2.78(3H, s), 2.88(2H, m), 2.92(3H, s),3.07–3.25(4H, m), 7.16(2H, d, J=8.5 Hz), 7.42(2H, d, J=8.5 Hz), 7.95(1H,t, J=5.52 Hz), 9.94(1H, s), 11.4(1H, s), 12.3(1H, s).

MS: 710(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.27–1.34(2H, m), 1.47(4H, m),2.16(3H, s), 2.26(2H, t, J=7.2 Hz), 2.79(3H, s), 2.94(3H, s),2.90–2.94(2H, m), 3.17(4H, m), 7.13(2H, d, J=8.3 Hz), 7.26(2H, d, J=8.3Hz), 7.47(4H, br), 8.05(1H, t, J=5.4 Hz), 9.93(1H, s).

MS: 488(M+H)⁺ free

PRODUCTION EXAMPLE 87 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[3-(4-morpholinyl)propyl]-1,3-thiazole-5-carboxamidedihydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[3-(4-morpholinyl)propyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.58(9H, br), 1.62(2H, m), 2.14(3H,s), 2.31(6H, m), 2.88(2H, m), 2.19(4H, m), 3.58(4H, m), 7.14(2H, d,J=8.4 Hz), 7.41(2H, d, J=8.4 Hz), 7.95(1H, t, J=5.2 Hz), 9.94(1H, s),11.45(1H, s), 12.30(1H, s).

MS: 696(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.90–2.00(2H, br), 2.17(3H, s),2.83–3.15(6H, m), 3.15–3.30(4H, m), 3.30–3.44(2H, m), 3.77–4.00(4H, m),7.14(2H, d, J=8.5 Hz), 7.26(2H, d, J=8.5 Hz), 7.44(4H, br), 8.20(1H, t,J=5.5 Hz), 9.92(1H, s), 11.01(1H, s), 12.38(1H, s).

MS: 474(M+H)⁺ free

PRODUCTION EXAMPLE 88 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[3-(2-oxo-1-pyrrolidinyl)propyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.41(9H, br), 1.49(9H, br), 1.64(2H,t, J=6.9 Hz), 1.90(2H, m), 2.14(3H, s), 2.17(2H, m), 2.91(2H, m),3.16(6H, m), 3.32(2H, m), 7.16(2H, d, J=8.4 Hz), 7.41(2H, d, J=8.4 Hz),7.93(1H, t, J=5.6 Hz), 9.93(1H, br), 11.73(1H, br).

MS: 694(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.65(2H, m), 1.91(2H, m), 2.16(3H,s), 2.20(2H, q, J=7.5 Hz), 2.90(2H, m), 3.02–3.27(6H, m), 3.33(2H, t,J=7.5 Hz), 7.16(2H, d, J=8.5 Hz), 7.26(2H, d, J=8.5 Hz), 8.03(1H, br),9.92(1H, s), 12.35(1H, s).

MS: 472(M+H)⁺ free

PRODUCTION EXAMPLE 89 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-hexyl-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[(hexylamino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from the compound obtained in Step 2.of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 0.85(3H, t, J=6.4 Hz), 1.25(9H, s),1.35–1.60(17H, br), 2.14(3H, s), 2.88(2H, m), 3.15(4H, m), 7.14(2H, d,J=8.5 Hz), 7.41(2H, d, J=8.5 Hz), 7.92(1H, t, J=5.7 Hz), 10.00(1H, br),11.60(1H, br).

MS: 653(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆ (+D₂O)), δ (ppm): 0.86(3H, t, J=6.53 Hz),1.18–1.57(8H, m), 2.16(3H, s), 2.91(2H, dd, J=9.5, 6.0 Hz), 3.16(4H, m),7.13(2H, d, J=8.5 Hz), 7.25(2H, d, J=8.5 Hz), 8.05(1H, br), 9.91(1H, s),12.33(1H, s).

MS: 431(M+H)⁺ free

PRODUCTION EXAMPLE 90 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[4-oxo-4-(1-piperidinyl)butyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[4-oxo-4-(1-piperidinyl)butyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.29–1.59(20H, m), 1.69(2H, m),2.14(3H, s), 2.30(2H, t, J=7.5 Hz), 2.89(4H, m), 3.32–3.45(4H, m),7.16(2H, d, J=8.0 Hz), 7.41(2H, d, J=8.0 Hz), 7.99(1H, t, J=5.2 Hz),9.94(1H, s), 11.43(1H, br).

MS: 722(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.30–1.79(8H, m), 2.16(3H, s),2.31(2H, t, J=7.5 Hz), 2.92(2H, m), 3.18(4H, m), 3.38(4H, m), 7.13(2H,d, J=8.0 Hz), 7.25(2H, d, J=8.0 Hz), 7.43(4H, br), 8.09(1H, t, J=6.0Hz), 9.87(1H, s), 12.34(1H, s).

MS: 500(M+H)⁺ free

PRODUCTION EXAMPLE 91 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[4-(4-morpholinyl)-4-oxobutyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[4-(4-morpholinyl)-4-oxobutyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared, from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.40(9H, s), 1.50(9H, s), 1.71(2H,m), 2.14(3H, s), 2.32(2H, t, J=7.3 Hz), 2.89(2H, dd, J=10.1, 6.9 Hz),3.19(4H, m), 3.42(4H, m), 3.51(4H, m), 7.16(2H, d, J=8.3 Hz), 7.42(2H,d, J=8.3 Hz), 7.99(2H, t, J=5.3 Hz), 9.94(1H, s), 11.44(1H, s),12.33(1H, s).

MS: 724(M+Na)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.70(2H, m), 2.16(3H, s), 2.33(2H,t, J=7.0 Hz), 2.91(2H, m), 3.19(4H, m), 3.42(4H, m), 3.53(4H, m),7.13(2H, d, J=8.5 Hz), 7.25(2H, d, J=8.5 Hz), 7.44(4H, br), 8.07(1H, t,J=5.0 Hz), 9.89(1H, s), 12.34(1H, s).

MS: 502(M+H)⁺ free

PRODUCTION EXAMPLE 92 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[4-(methylsulfonyl)phenyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[4-(methylthio)phenyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.18(3H,s), 2.45(3H, s), 2.82–3.00(2H, m), 3.17–3.30(2H, m), 7.13(2H, d, J=8.5Hz), 7.23(2H, d, J=8.5 Hz), 7.41(2H, d, J=8.5 Hz), 7.61(2H, d, J=8.5Hz), 9.92(2H, s), 11.43(1H, s), 12.45(1H, s).

MS: 691(M+Na)⁺

Step 2

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[4-(methylsulfonyl)phenyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in a similar manner according to Step 2 of ProductionExample 32.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.39(9H, s), 1.51(9H, s), 2.18(3H,s), 2.81–3.03(2H, m), 3.18(3H, s), 3.19–3.30(2H, m), 7.16(2H, d, J=8.5Hz), 7.41(2H, d, J=8.5 Hz), 7.86(2H, d, J=9.0 Hz), 7.93(2H, d, J=9.0Hz), 9.92(1H, s), 10.34(1H, s), 11.42(1H, s), 12.52(1H, s).

MS: 723(M+Na)⁺

Step 3

The title compound was prepared in a similar manner according to Step4-of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.20(3H, s), 2.84–3.07(2H, m),3.17–3.32(2H, m), 3.18(3H, s), 7.12(2H, d, J=8.5 Hz), 7.37(4H, br),7.86(2H, d, J=9.0 Hz), 7.92(2H, d, J=9.0 Hz), 9.76(1H, s), 10.42(1H, s).

MS: 501(M+H)⁺ free

PRODUCTION EXAMPLE 93 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[(1S)-2-(dimethylamino)-1-methyl-2-oxoethyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[(1S)-2-(dimethylamino)-1-methyl-2-oxoethyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 1.40(3H, d, J=7.0 Hz), 1.49(9H, s),1.53(9H, s), 2.22(3H, s), 2.95(2H, m), 3.00(3H, s), 3.10(3H, s),3.26(2H, m), 5.01(1H, dt, J=7.0 Hz), 6.87(1H, d, J=7.5 Hz), 7.14(2H, d,J=8.5 Hz), 7.40(2H, d, J=8.5 Hz), 9.57(1H, br), 10.20(1H, s), 11.62(1H,s).

MS: 646(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.23(3H, d), 2.16(3H, s), 2.84(3H,s), 2.87–2.95(2H, m), 3.03(3H, s), 3.15–3.24(2H, m), 3.56(1H, s),4.78(3H, t, J=7.0 Hz), 7.13(2H, d, J=8.4 Hz), 7.25(2H, d, J=8.4 Hz),8.09(1H, d, J=7.0 Hz), 9.67(1H, s), 12.35(1H, s).

MS: 446(M+H)⁺ free

PRODUCTION EXAMPLE 94 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[(1S)-1-benzyl-2-(dimethylamino)-2-oxoethyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[(1S)-1-benzyl-2-(dimethylamino)-2-oxoethyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 1.48(9H, s), 1.52(9H, s), 2.22(3H, s),2.68(3H, s), 2.84–2.97(5H, m)-, 3.06(2H, d, J=7.5 Hz), 3.17(H, dd,J=8.0, 6.0 Hz), 5.26(1H, q, J=7.5 Hz), 6.80(1H, d, J=8.0 Hz), 7.08(2H,d, J=8.0 Hz), 7.14–7.33(5H, m), 7.39(2H, d, J=8.0 Hz), 9.96(1H, br),10.19(1H, s), 11.61(1H, s). MS. 722(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.15(3H, s), 2.82–3.15(13H, m),4.91(1H, q, J=6.7 Hz), 7.09(4H, s), 7.16–7.31(5H, m), 7.36(4H, br),8.31(1H, d, J=7.7 Hz), 9.71(1H, s), 12.33(1H, s).

MS: 522(M+H)⁺ free

PRODUCTION EXAMPLE 95 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-[(1S)-2-(dimethylamino)-1-(hydroxymethyl)-2-oxoethyl]-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({[(1S)-2-(dimethylamino)-1-(hydroxymethyl)-2-oxoethyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 1.48(9H, s), 1.52(9H, s), 2.23(3H, s),2.94(2H, dd, J=7.0 Hz), 3.01(3H, s), 3.14(3H, s), 3.26(2H, dd, J=7.0Hz), 3.78–3.86(3H, br), 5.04(1H, m), 6.85(1H, d, J=7.5 Hz), 7.08(2H, d,J=8.5 Hz), 7.37(2H, d, J=8.5 Hz), 9.70(1H, br), 10.20(1H, s), 11.61(1H,s).

MS: 662(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.16, 2.19(3H, s ×2), 2.85–3.50(10H,m), 3.60–3.69(2H, m), 4.81(1H, m), 7.14(2H, m), 2.27(2H, m), 7.39(4H,br), 7.91(1H, br), 8.48(1H, br), 9.77, 9.94(1H, s ×2), 12.37, 12.61(1H,s ×2).

MS: 462(M+H)⁺ free

PRODUCTION EXAMPLE 96 Synthesis of2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-N-{(1S,2S)-1-[(dimethylamino)carbonyl]-2-hydroxypropyl}-1,3-thiazole-5-carboxamidehydrochloride

Step 1

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[({(1S,2S)-1-[(dimethylamino)carbonyl]-2-hydroxypropyl)amino}carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 1.18(3H, d, J=6.5 Hz), 1.48(9H, s),1.52(9H, s), 2.22(3H, s), 2.95(2H, m), 2.99(3H, s), 3.16(3H, s),3.20–3.32(2H, m), 4.06–4.12(2H, m), 5.02(1H, dd, J=9.0, 1.5 Hz),6.55(1H, d, J=9.0 Hz), 7.09(2H, d, J=8.0 Hz), 7.38(2H, d, J=8.0 Hz),9.70(1H, br), 10.20(1H, s), 11.62(1H, s).

MS: 676(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.35(3H, d, J=6.5 Hz), 2.19(3H, s),2.85–2.97(6H, m), 3.11(3H, s), 3.26(2H, m), 4.67(1H, br), 5.40(1H, m),7.15(2H, d, J=8.3 Hz), 7.28(2H, d, J=8.3 Hz), 7.43(4H, br), 8.43(3H,br), 9.93(1H, s), 12.59(1H, s).

MS: 475(M+H)⁺ free

PRODUCTION EXAMPLE 97 Synthesis of(2S)-2-[({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}carbonyl)amino]-N¹,N¹-dimethylpentanediamidehydrochloride

Step 1

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[({(1S)-4-amino-1-[(dimethylamino)carbonyl]-4-oxobutyl}amino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from the compound obtained in Step 2 of Production Example34 in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 1.49(9H, s), 1.53(9H, s),1.86–2.19(2H, m), 2.22–2.37(5H, m), 2.89(2H, m), 2.99(3H, s),3.05–3.16(5H, m), 3.20–3.41(1H, m), 5.06(1H, m), 6.27(1H, br), 6.35(1H,br), 6.81(1H, d, J=7.5 Hz), 7.09(2H, d, J=8.5 Hz), 7.41(2H, d, J=8.5Hz), 10.21(1H, s), 10.55(1H, br), 11.62(1H, s).

MS: 703(M+H)⁺

Step 2

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.70–2.00(2H, m), 2.16(5H, m),2.84(3H, s), 2.91(2H, m), 3.08(3H, s), 3.19(2H, m), 4.75(1H, m),6.79(1H, m), 7.12(2H, d, J=8.3 Hz), 7.25(2H, d, J=8.3 Hz), 7.39(4H, br),8.13(1H, d), 9.77(1H, s), 12.35(1H, s).

MS: 503(M+H)⁺ free

PRODUCTION EXAMPLE 98 Synthesis ofN-{4-[2-(4-{[imino(methylamino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared from the compound obtained in Step 2 ofProduction Example 50 in a similar manner according to ProductionExample 58.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.79(3H, s), 2.86(4H, s),3.18(3H, s), 4.08(2H, s), 4.43(2H, m), 7.08(2H, d, J=8.5 Hz), 7.22(2H,d, J=8.5 Hz), 7.39(2H, d, J=8.5 Hz), 7.85(2H, d, J=8.5 Hz), 12.05(1H,brs).

MS: 486(M+H)⁺

PRODUCTION EXAMPLE 99 Synthesis of(2S)-1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)-N,N-dimethyl-2-pyrrolidinecarboxamidedihydrochloride

Step 1

tert-Butyl{4-[2-(2-(acetylamino)-5-{[methoxy(methyl)amino]carbonyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamatewas prepared from2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylicacid in a similar manner according to Step 1 of Production Example 32.

¹H-NMR (CDCl₃), δ (ppm): 1.46(9H, s), 2.15(3H, s), 2.74–2.93(2H, m),3.12–3.29(2H, m), 3.22(3H, s), 3.59(3H, s), 7.05(2H, d, J=8.5 Hz),7.33(2H, d, J=8.5 Hz), 9.21(1H, s), 12.34(1H, s).

MS: 471.1(M+Na)⁺

Step 2

To a solution of the compound obtained in Step 1 (3.93 g) in THF (80 mL)was added lithium aluminium hydirde (499 mg) slowly (over 15 min) at5–10° C. (under ice-cooling). The mixture was stirred at 5° C. for 1 h.30 mL of aquaous solution of sodium pottasium tartrate (1M) was addedslowly under ice-cooling, and then the mixture was stirred for another0.5 h at r.t. The mixture was extracted with ethyl acetate, and theorganic layer was dried over MgSO₄, and concecntrated in vacuo to givepale yellow oil. This oil was triturated with IPE and EtOAc to givetert-butyl(4-{2-[2-(acetylamino)-5-formyl-1,3-thiazol-4-yl]ethyl}phenyl)carbamateas pale yellow powder (2.67 g).

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.46(9H, s), 2.19(3H, s), 2.90(2H,t, J=7.3 Hz), 3.22(2H, t, J=7.3 Hz), 7.01(2H, d, J=8.5 Hz), 7.32(2H, d,J=8.5 Hz), 9.22(1H, s), 9.77(1H, s), 12.68(1H, s).

MS: 390(M+H)⁺

Step 3

To a solution of the compound obtained in Step 2 (200 mg) indichloromethane (6 mL) were added(2S)-2-(N,N-dimethylaminocarbonyl)pyrrolidine hydrochloride anddiisopropylethylamine (0.27 ml) at 5° C. The mixture was stirred at 5°C. for 10 min. Then sodium triacetoxyborohydride (327 mg) was added, andthe mixture was stirred for 3 hrs. aq. NH₄Cl was added, and the mixuturewas extracted with dichloromethane. The organic layer was dried overMgSO₄. The layer was concentrated under reduced pressure. The resultingcrude mixture was purified by silica gel column chlomatography withmixed solvent (dichloromethane/methanol=15/1) as an eluent to givetert-butyl(4-{2-[2-(acetylamino)-5-({(2S)-2-[(N,N-dimethylamino)carbonyl]-1-pyrrolidinyl}methyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamateas a pale yellow amorphous substance.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 1.67–1.99(4H, m), 2.24(3H, s),2.04(4H, s), 2.14(3H, s), 2.95–3.14(5H, m), 3.42–3.58(2H, m),3.68–3.83(1H, m), 6.97(2H, d, J=8.3 Hz), 7.94(2H, d, J=8.3 Hz).

MS: 516(M+H)⁺

Step 4

(2S)-1-({2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-5-yl}methyl)-N,N-dimethyl-2-pyrrolidinecarboxamidewas prepared in a similar manner according to Step 2 of ProductionExample 31.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 1.70–2.10(4H, m), 2.22(3H, s),2.39(1H, q, J=8.4 Hz), 2.77(4H, m), 2.91(3H, s), 3.03(3H, s),3.30–3.81(6H, m), 6.58(2H, d, J=8.3 Hz), 6.89(2H, d, J=8.3 Hz), 8.82(1H,br).

MS: 416(M+H)⁺

Step 5

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({(2S)-2-[(N,N-dimethylamino)carbonyl]-1-pyrrolidinyl}methyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 1.50(9H, s), 1.52(9H, s),1.76–1.92(4H, m), 2.04–2.14(1H, m), 2.43(1H, dd, J=8.1, 8.0 Hz),2.45(3H, s), 2.85(2H, s), 3.07(3H, s), 3.51(1H, dd, J=5.7, 8.0 Hz),3.60(1H, d, J=14.3 Hz), 3.84(1H, d, J=14.3 Hz), 6.37(1H, t, J=2.0 Hz),7.08(2H, d, J=8.4 Hz), 7.44(2H, d, J=8.4 Hz), 7.63(1H, d, J=2.0 Hz),10.23(1H, s), 11.62(1H, br).

MS: 658(M+H)⁺

Step 6

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 1.60–1.98(2H, br), 1.98–2.16(1H,br), 2.16(3H, s), 2.85(3H, s), 2.95(7H, br), 3.00–3.30(1H, br), 7.15(2H,d, J=8.3 Hz), 7.30(2H, d, J=8.3 Hz), 7.55(4H, br), 7.85(1H, d, J=2.2Hz), 9.65(1H, br), 10.21(1H, s), 12.35(1H, s).

MS: 458(M+H)⁺ free

PRODUCTION EXAMPLE 100 Synthesis of3-[({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)(methyl)amino]-N,N-dimethylpropanamidedihydrochloride

Step 1

tert-Butyl(4-{2-[2-(acetylamino)-5-({[3-(N,N-dimethylamino)-3-oxopropyl]amino}methyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamatewas prepared from the compound obtained in Step 2 of Production Example99 in a similar manner according to Step 3 of Production Example 99.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 1.50(9H, s), 2.24(3H, s), 2.47(2H, t,J=6.2 Hz), 2.74(2H, t, J=6.2 Hz), 2.82–2.88(4H, m), 2.93(3H, s),2.97(3H, s), 3.59(2H, s), 6.94(2H, d, J=8.3 Hz), 7.21(2H, d, J=8.3 Hz),8.02(1H, s).

MS: 490(M+H)⁺

Step 2

To a solution of the compound obtained in Step 1 (100 mg) indichloromethane (1.5 mL) was added formaline (35%, 87.6 μl). To thissuspension was added 0.05 ml of MeOH. Then, sodium triacetoxyborohydride(433 mg) was added, and the mixture was stirred for 12 hrs. To themixture were added water and 1N NaOH to adjust pH of aquaous phase (ca.pH 8–9). The mixture was extracted with dichloromethane. The organiclayer was dried with MgSO₄ and concentrated under redused pressure.Resulting oil was purified by silica gel column chromatograph (mixedsolvent of CH₂Cl₂/MeOH 15/1 as an eluent) to give tert-butyl{4-[2-(2-(acetylamino)-5-{[[3-(N,N-dimethylamino)-3-oxopropyl](methyl)amino]methyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamateas pale yellow oil (90.4 mg).

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 1.51(9H, s), 2.18(3H, s), 2.24(3H, s),2.45(2H, m), 2.62(2H, m), 2.80(4H, s), 2.93(3H, s), 2.99(3H, s),3.35(2H, s), 6.96(2H, d, J=8.3 Hz), 7.20(2H, d, J=8.3 Hz).

MS: 504(M+H)⁺

Step 3

3-[({2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-5-yl}methyl)(methyl)amino]-N,N-dimethylpropanamidewas prepared in a similar manner according to Step 2 of ProductionExample 31.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 2.19(3H, s), 2.22(2H, s),2.43–2.51(2H, m), 2.62–2.71(4H, m), 2.78(3H, s), 2.93(3H, s), 2.99(3H,s), 3.33(2H, s), 3.65(1H, m), 3.75(1H, m), 6.58(2H, d, J=8.3 Hz),6.87(2H, d, J=8.3 Hz).

MS: 404(M+H)⁺

Step 4

Di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{[[3-(N,N-dimethylamino)-3-oxopropyl](methyl)amino]methyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared in a similar manner according to Step 3 of ProductionExample 31.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 1.50(9H, s), 1.53(9H, s), 2.20(3H, s),2.22(3H, s), 2.49(2H, dd, J=6.5, 5.5 Hz), 2.71(2H, dd, J=6.5, 5.5 Hz),2.84(4H, s), 2.93(3H, s), 2.99(3H, s), 3.43(2H, s), 7.08(2H, d, J=8.4Hz), 7.46(2H, d, J=8.4 Hz), 7.62(1H, s), 10.24(1H, s), 11.62(1H, s).

MS: 646(M+H)⁺

Step 5

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.15(3H, s), 2.68(3H, d, J=4.0 Hz),2.83–2.88(6H, m), 2.96(6H, s), 3.05–3.15(2H, m), 4.44(2H, m), 7.15(2H,d, J=8.3 Hz), 7.32(2H, d, J=8.3 Hz), 7.62(4H, br), 9.90(1H, s),12.32(1H, s).

MS: 446(M+H)⁺ free

PRODUCTION EXAMPLE 101 Synthesis of4-(2-{2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}ethyl)-N,N-dimethylbenzamidehydrochloride

Step 1

Methyl4-{2-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]vinyl}benzoatewas prepared from the compound obtained in Step 2 of Production Example99 in a similar manner according to Step 1 of Production Example 53.

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H× 4/9, s), 1.51(9H× 5/9, s), 2.20(3H×5/9, s), 2.29(3H× 4/9, s), 2.72–3.06(4H, m), 3.90(3H× 5/9, s), 3.92(3H×4/9, s), 6.42–6.60(2H× 5/9, m), 6.69(1H× 4/9, d, J=16.6 Hz),6.81–7.03(4H +1H× 4/9, m), 7.31(2H× 5/9, d, J=8.0 Hz), 7.39(2H× 4/9, d,J=8.0 Hz), 7.96(2H× 5/9, d, J=8.0 Hz), 7.99(2H× 4/9, d, J=8.0 Hz).

MS: 522.2(M+H)⁺, 544.2(M+Na)⁺

Step 2

Methyl4-{2-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]ethyl}benzoatewas prepared in a similar manner according to Step 6 of ProductionExample 45.

MS: 524.25(M+H)⁺

Step 3

4-{2-[2-(Acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]ethyl}benzoicacid was prepared in a similar manner according to Step 2 of ProductionExample 65.

¹H-NMR (DMSO-d₆), δ (ppm): 1.45(9H, s), 2.09(3H, s), 2.57–2.72(6H, m),2.75–2.86(2H, m), 6.94(2H, d, J=8.4 Hz), 7.21(2H, d, J=8.4 Hz), 7.32(2H,d, J=8.4 Hz), 7.82(2H, d, J=8.4 Hz), 9.21(1H, s), 11.94(1H, s),12.41–13.20(1H, brs).

MS: 510.2(M+H)⁺, 532.2(M+Na)⁺

Step 4

tert-Butyl(4-{2-[2-(acetylamino)-5-(2-{4-[(methylamino)carbonyl]phenyl}ethyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamatewas prepared in a similar manner according to Step 3 of ProductionExample 65.

¹H-NMR (CDCl₃), δ (ppm): 1.51(9H, s), 2.24(3H, s), 2.56–2.73(4H, m),2.73–2.86(4H, m), 2.99(3H, d, J=4.8 Hz), 6.05(1H, d, J=4.4 Hz),6.25–6.75(1H, brs), 6.77(2H, d, J=6.6 Hz), 7.12(2H, d, J=8.1 Hz),7.15–7.23(2H, m), 7.63(2H, d, J=8.1 Hz), 8.43–9.18(1H, brs).

MS: 523.29(M+H)⁺

Step 5

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-(2-{4-[(methylamino)carbonyl]phenyl}ethyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in a similar manner according to Step 4 of ProductionExample 65.

¹H-NMR (CDCl₃), δ (ppm): 1.48(9H, s), 1.54(9H, s), 2.22(3H, s),2.51–2.61(2H, m), 2.61–2.71(2H, m), 2.79–2.90(4H, m), 2.97(3H, d, J=4.8Hz), 6.20(1H, d, J=4.8 Hz), 6.98(2H, d, J=8.4 Hz), 7.13(2H, d, J=8.1Hz), 7.40(2H, d, J=8.4 Hz), 7.64(2H, d, J=8.4 Hz), 8.83–9.42(1H, brs),10.21(1H, s), 11.62(1H, s).

MS: 687.2(M+Na)⁺

Step 6

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.58–2.79(6H, m), 2.80–3.02(8H,m), 7.13(2H, d, J=8.4 Hz), 7.19(2H, d, J=8.1 Hz), 7.20(2H, d, J=8.4 Hz),7.29(2H, d, J=8.1 Hz), 7.32(4H, s), 9.66(1H, s), 11.93(1H, s).

MS: 479.2(M+H)⁺ free

PRODUCTION EXAMPLE 102 Synthesis of4-(2-{2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}ethyl)-N-methylbenzamidehydrochloride

Step 1

tert-Butyl(4-{2-[2-(Acetylamino)-5-(2-{4-[(dimethylamino)carbonyl]phenyl}ethyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamatewas prepared from the compound obtained in Step 3 of Production Example101 in a similar manner according to Step 3 of Production Example 65.

¹H-NMR (CDCl₃), δ (ppm): 1.51(9H, s), 2.23(3H, s), 2.66(4H, s), 2.79(4H,s), 2.93(3H, s), 3.08(3H, s), 6.90(2H, d, J=8.0 Hz), 7.11(2H, d, J=8.0Hz), 7.18(2H, d, J=8.0 Hz), 8.56–10.01(1H, brs).

MS: 537(M+H)⁺, 559.2(M+Na)⁺

Step 2

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-(2-{4-[(dimethylamino)carbonyl]phenyl}ethyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared in a similar manner according to Step 4 of ProductionExample 65.

¹H-NMR (CDCl₃), δ (ppm): 1.49(9H, s), 1.53(9H, s), 2.21(3H, s),2.57–2.78(4H, m), 2.82(4H, s), 2.94(3H, s), 3.08(3H, s), 7.03(2H, d,J=8.5 Hz), 7.13(2H, d, J=8.0 Hz), 7.33(2H, d, J=8.0 Hz), 7.45(2H, d,J=8.5 Hz), 8.28–9.61(1H, brs), 10.24(1H, s), 11.63(1H, s).

MS: 679.2(M+H)⁺, 701.2(M+Na)⁺

Step 3

The title compound was prapared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.10(3H, s), 2.60–2.72(4H, m), 2.72–2.80(2H,m), 2.76(3H, d, J=4.4 Hz), 2.89(2H, t, J=7.3 Hz), 7.12(2H, d, J=8.4 Hz),7.19(2H, d, J=8.4 Hz), 7.22(2H, d, J=8.1 Hz), 7.33(4H, s), 7.73(2H, d,J=8.1 Hz), 8.36(1H, d, J=4.4 Hz), 9.66(1H, s), 11.93(1H, s).

MS: 465.2(M+H)⁺ free

PRODUCTION EXAMPLE 103 Synthesis of methylN-[4-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)phenyl]carbamatehydrochloride

Step 1

To a suspension of4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]methyl}benzoicacid (50 mg) in toluene (0.5 ml) and dioxane (0.5 ml) were addedtriethylamine (28.1 μl) and diphenylphosphoryl azide (39.1 μl), and themixture was stirred at 25° C. for 2 hrs., then stirred at 100° C. for 1h. To the reaction mixture was added methanol (1 ml), and the mixturewas refluxed for 2 hrs., and concentrated in vacuo. The residue waspurified by preparative thin-layer chromatography over silica gel withchloroform/methanol (20:1) as an eluent to give methylN-(4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]methyl}phenyl)carbamate(17.2 mg).

¹H-NMR (CDCl₃), δ (ppm): 1.52(9H, s), 2.22(3H, s), 2.80(4H, s), 3.76(3H,s), 3.79(2H, s), 6.62–6.78(1H, brs), 6.83–7.05(1H, brs), 6.90(2H, d,J=8.0 Hz), 6.98(2H, d, J=8.5 Hz), 7.17(2H, d, J=8.0 Hz), 7.20–7.33(2H,m).

MS: 547.2(M+Na)⁺

Step 2

Di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{4-[(methoxycarbonyl)amino]benzyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared in a similar manner according to Step 4 of ProductionExample 65.

¹H-NMR (CDCl₃), δ (ppm): 1.49(9H, s), 1.54(9H, s), 2.19(3H, s), 2.82(4H,s), 3.76(3H, s), 3.80(2H, s), 6.72–6.90(1H, brs), 6.98(2H, d, J=8.5 Hz),7.00(2H, d, J=8.5 Hz), 7.26(2H, d, J=8.5 Hz), 7.39(2H, d, J=8.5 Hz),9.10–9.59(1H, brs), 10.19(1H, s), 11.64(1H, s).

MS: 667.2(M+H)⁺, 689.2(M+Na)⁺

Step 3

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.08(3H, s), 2.85(4H, s), 3.64(3H, s),3.85(2H, s), 7.04(2H, d, J=8.5 Hz), 7.14(2H, d, J=8.4 Hz), 7.24(2H, d,J=8.4 Hz), 7.28–7.47(6H, m), 9.58(1H, s), 9.70(1H, s), 11.96(1H, s).

MS: 467.2(M+H)⁺

PRODUCTION EXAMPLE 104 Synthesis of ethyl1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)-4-piperidinecarboxylatedihydrochloride

Step 1

Ethyl1-({2-(acetylamino)-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-5-yl}methyl)-4-piperidinecarboxylatewas prepared fromN-{4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide in asimilar manner according to Step 1 of Production Example 67.

MS: 459.17(M+H)⁺

Step 2

Ethyl1-[(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)methyl]-4-piperidinecarboxylatewas prepared in a similar manner according to Step 2 of ProductionExample 68.

¹H-NMR (CDCl₃), δ (ppm): 1.24(3H, t, J=7.2 Hz), 1.50(9H, s), 1.53(9H,s), 1.65–2.09(6H, m), 2.13–2.34(4H, s), 2.71–2.95(6H, m), 3.39(2H, s),4.12(2H, q, J=7.2 Hz), 7.07(2H, d, J=8.5 Hz), 7.46(2H, d, J=8.5 Hz),10.24(1H, s), 11.63(1H, brs).

MS: 673.3(M+H)⁺, 695.3(M+Na)⁺

Step 3

The title compound was prepared in a similar manner according to Step 4of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.18(3H, t, J=7.1 Hz), 1.73–1.90(2H, m),1.93–2.13(2H, m), 2.16(3H, s), 2.87–3.01(6H, m), 3.30–3.41(2H, m),4.08(2H, q, J=7.1 Hz), 4.31–4.43(2H, m), 7.15(2H, d, J=8.4 Hz), 7.31(2H,d, J=8.4 Hz), 7.42(4H, s), 9.90(1H, s), 10.23–10.46(1H, brs), 12.3(1H,s).

MS: 473.2(M+H)⁺, 495.2(M+Na)⁺ free

PRODUCTION EXAMPLE 105 Synthesis of ethyl1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)-4-piperidinecarboxylatehydrochloride

The title compound was prepared in a similar manner according to Example104.

PRODUCTION EXAMPLE 106 Synthesis of4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)-N-[amino(imino)methyl]benzamide

Guanidine hydrochloride (152 mg) was dissolved in DMF (3 ml), and then28% sodium methoxide methanol solution (0.3 ml) was added to thesolution at r.t. The suspension was stirred at r.t. for 15 minutes, andmethyl4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)benzoate(150 mg) was added to the mixture at r.t. The reaction mixture wasstirred at r.t. for 14.hours, and concentrated in vacuo. The residue wasdissolved in water, and neutralized with 1N-HCl. The precipitate wascollected through filtration, and purified by preparative silica gelchromatography with CHCl₃/MeOH (10:1) as an eluent. The solid was washedwith ethyl ether to give4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)-N-[amino(imino)methyl]benzamide(36.6 mg) as an off-white solid.

mp. 108–109.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.89(4H, s), 3.16(3H, s),4.06(2H, s), 7.15(2H, d, J=8.0 Hz), 7.27(2H, d, J=8.0 Hz), 7.78(2H, d,J=8.0 Hz), 7.95(2H, d, J=8.0 Hz), 12.04(1H, s).

MS: 500(M+H)⁺

PRODUCTION EXAMPLE 107 Synthesis of tert-butyl(2-{[4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}-2-oxoethyl)carbamate

The title compound was prepared from2-(acetylamino)-4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazolin a similar manner according to Step 1 of Production Example 10.

mp. 186–187.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.39(9H, s), 2.08(3H, s), 2.84(4H, s),3.17(3H, s), 3.71(2H, d, J=6.0 Hz), 4.00(2H, s), 7.01(1H, t, J=6.0 Hz),7.06(2H, d, J=8.5 Hz), 7.28(2H, d, J=8.5 Hz), 7.46(2H, d, J=8.5 Hz),7.79(2H, d, J=8.5 Hz), 9.86(1H, s), 12.04(1H, s).

MS: 587(M+H)⁺

PRODUCTION EXAMPLE 108 Synthesis ofN-[4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]-2-aminoacetamidehydrochloride

The title compound was prepared from the compound of Production Example107 in a similar manner according to Step 2 of Production Example 10.

mp. 142.5–144° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.09(3H, s), 2.85(4H, s), 3.18(3H, s),3.78(2H, m), 4.00(2H, s), 7.10(2H, d, J=8.5 Hz), 7.26(2H, d, J=8.5 Hz),7.50(2H, d, J=8.5 Hz), 7.79(2H, d, J=8.5 Hz), 8.22(3H, brs), 10.63(1H,s), 12.06(1H, s).

MS: 487(M+H)⁺ free

PRODUCTION EXAMPLE 109 Synthesis ofN-(4-{2-[4-(2-aminoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamidehydrochloride

Step 1

N-(4-{2-[4-(Cyanomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (1 g),1N-NaOH (7 ml) and EtOH (14 ml) were combined, and the reaction mixturewas refluxed for 8 hours. After cooled to r.t., the organic solvent wasremoved in vacuo. The aqueous solution was neutralized with 1N-HCl, andextracted with AcOEt. The organic layer was washed with water and brine,dried over anhydrous MgSO₄, and concentrated in vacuo. The residualyellow wax (1.03 g) was dissolved in THF (10 ml), and then lithiumaluminium hydride (266 mg) was added to the solution at 0° C. Thereaction mixture was refluxed for 3 hours, and quenched with MeOH. ThenNa₂SO₄/10H₂O was added to the mixture, the mixture was stirred at r.t.for 1 hour and filtered through a celite pad. The filtrate wasconcentrated in vacuo. The residual yellow amorphous (835.5 mg) wasdissolved in THF (10 ml) and DMF (10 ml) under N₂ atmosphere. Thendi(tert-butyl) dicarbonate (841 mg) in THF (5 ml) was added to thesolution at r.t. The reaction mixture was stirred at r.t. for 12 hours,and concentrated in vacuo to give tert-butyl(2-{4-[2-(2-amino-1,3-thiazol-4-yl)ethyl]phenyl}ethyl)carbamate (171.6mg) as yellow oil.

¹H-NMR (DMSO-d₆), δ (ppm): 1.38(9H, s), 2.60–2.70(4H, m), 2.79–2.88(4H,m), 6.82(1H, s), 7.07(2H, d, J=8.0 Hz), 7.11(2H, d, J=8.0 Hz).

MS: 348(M+H)⁺

Step 2

tert-Butyl[2-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethyl]carbamatewas prepared from the compound of Step 1 in a similar manner accordingto Step 3 of Production Example 45.

¹H-NMR (DMSO-d₆), δ (ppm): 1.36(9H, s), 2.11(3H, s), 2.58–2.70(1H, m),2.80–2.97(6H, m), 3.02–3.18(1H, m), 6.72(1H, s), 7.08(2H, d, J=8.0 Hz),7.23(2H, d, J=8.0 Hz), 12.08(1H, s).

MS: 390(M+H)⁺

Step 3

The title compound was prepared from the compound of Step 2 in a similarmanner according to Step 2 of Production Example 10.

mp. 165–167° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.12(3H, s), 2.79–3.09(8H, m), 6.75(1H, s),7.16(4H, s), 8.14(2H, brs), 12.13(1H, brs).

MS: 290(M+H)⁺ free

PRODUCTION EXAMPLE 110 Synthesis ofN-(4-{2-[4-(2-{[amino(imino)methyl]amino}ethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamidehydrochloride

Step 1

N-(4-{2-[4-(2-Aminoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamidehydrochloride (7 mg),N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (6.57 mg),N,N-diisopropylethylamine (0.00748 ml), THF (0.5 ml) and DMF (0.1 ml)were combined under N₂ atmosphere. The reaction mixture was stirred atr.t. for 43 hours, and concentrated in vacuo. The residue was purifiedby preparative silica gel chromatography with n-hexane/AcOEt (1:1) as aneluent to give di-tert-butyl((Z)-{[2-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethyl]amino}methylidene)biscarbamate(5.9 mg) as colorless oil.

¹H-NMR [CD₃Cl/CD₃OD (1:1)], δ (ppm): 1.50(18H, s), 2.24(3H, s), 2.86(2H,t, J=7.0 Hz), 2.95(4H, s), 3.62(2H, t, J=7.0 Hz), 4.24(2H, s), 6.50(1H,s), 7.11(2H, d, J=8.5 Hz), 7.16(2H, d, J=8.5 Hz).

MS: 532(M+H)+

Step 2

The title compound was prepared from the compound of Step 1 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR [CD₃Cl/CD₃OD (1:1)], δ (ppm): 2.41(3H, s), 2.87(2H, t, J=7.0 Hz),3.05(4H, s), 3.44(2H, t, J=7.0 Hz), 6.86(1H, s), 7.18(4H, s).

MS: 332(M+H)⁺ free

PRODUCTION EXAMPLE 111 Synthesis ofN-(4-{4-[(2-{[amino(imino)methyl]amino}ethyl)sulfonyl]phenyl}-1,3-thiazol-2-yl)acetamidehydrochloride

Step 1

1-[4-(Methylthio)phenyl]ethanone (5.5 g) was dissolved in AcOH (55 ml),and then 90% pyridinium tribromide (11.8 g) and 30% hydrobromic acid inAcOH (5.5 ml) were added to the solution at 0° C. The reaction mixturewas stirred at r.t. for 30 minutes, and poured into water. The mixturewas extracted with AcOEt. The organic layer was washed with saturatedNaHCO₃ and brine, dried over anhydrous MgSO₄, and concentrated in vacuo.The residual solid (8.03 g), thiourea (3.78 g) and EtOH (55 ml) werecombined. The reaction mixture was refluxed for 1.5 hours under N₂atmosphere. After cooled to r.t., the precipitate was filtered in vacuo.The solid was washed with EtOH and water to give4-[4-(methylthio)phenyl]-1,3-thiazol-2-amine (7.48 g) as a pale yellowsolid.

mp. 245–246° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.51(3H, s), 7.18(1H, s), 7.35(2H, d, J=8.5Hz), 7.67(2H, d, J=8.5 Hz).

MS: 223(M+H)⁺

Step 2

N-{4-[4-(Methylthio)phenyl]-1,3-thiazol-2-yl}acetamide was prepared fromthe compound of Step 1 in a similar manner according to Step 3 ofProduction Example 45.

mp. 235–236° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 2.50(3H, s), 7.31(2H, d, J=8.5Hz), 7.56(1H, s), 7.83(2H, d, J=8.5 Hz), 12.24(1H, brs).

MS: 265(M+H)⁺

Step 3

N-{4-[4-(Methylthio)phenyl]-1,3-thiazol-2-yl}acetamide (2 g) wassuspended in CH₂Cl₂ (20 ml), and then 3-chloroperoxybenzoic acid (1.44g) was added portionwise to the suspension at 0° C. The reaction mixturewas stirred at r.t. for 15 minutes. The precipitate was filtered invacuo, and the solid was washed with 1N—Na₂CO₃, water and EtOH to giveN-{4-[4-(methylsulfinyl)phenyl]-1,3-thiazol-2-yl}acetamide (2.80 g) as acolorless solid.

mp. 274–274.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.10(3H, s), 2.77(3H, s), 7.62(1H, s),7.71(2H, d, J=8.5 Hz), 8.07(2H, d, J=8.5 Hz).

MS: 279(M−H)⁺

Step 4

N-{4-[4-(Methylsulfinyl)phenyl]-1,3-thiazol-2-yl}acetamide (1.5 g),sodium acetate (1.54 g), and acetic anhydride (30 ml) were combinedunder N₂ atmosphere. The reaction mixture was refluxed for 2 hours.After cooled to r.t., the mixture was diluted in AcOEt. The organicsolution was washed with water and brine, dried over anhydrous MgSO₄,and concentrated in vacuo. The residual solid was washed with ethylether/n-hexane to give({4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}thio)methyl acetate (811.2mg) as an off-white solid.

mp. 144–145° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.07(3H, s), 2.17(3H, s), 5.53(2H, s),7.50(2H, d, J=8.5 Hz), 7.63(1H, s), 7.88(2H, d, J=8.5 Hz), 12.27(1H,brs).

MS: 323(M+H)⁺

Step 5

({4-[2-(Acetylamino)-1,3-thiazol-4-yl]phenyl}thio)methyl acetate (40 mg)was dissolved in CH₂Cl₂ (0.6 ml) and MeOH (0.3 ml) under N₂ atmosphere.Then magnesium monoperoxyphthalate (120 mg) was added to the solution at0° C. The reaction mixture was stirred at r.t. for 2 hours. Water andCHCl₃ were added to the mixture, and the mixture was extracted. Theorganic layer was washed with saturated NaHCO₃ and brine, dried overanhydrous MgSO₄, and concentrated in vacuo. The residual solid waswashed with ethyl ether to give({4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl }sulfonyl)methyl acetate(29.7 mg) as a colorless solid.

mp. 237–238° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.07(3H, s), 2.18(3H, s), 5.43(2H, s),7.94(1H, s), 7.97(2H, d, J=8.5 Hz), 8.17(2H, d, J=8.5 Hz), 12.37(1H,brs).

MS: 355(M+H)⁺

Step 6

({4-[2-(Acetylamino)-1,3-thiazol-4-yl]phenyl}sulfonyl)methyl acetate(700 mg), THF (8 ml), MeOH (4 ml) and 1N—NaOH (1.98 ml) were combined.The reaction mixture was stirred at r.t. for 1.5 hours, and concentratedin vacuo. The residual solid was washed with ethyl ether to give sodium4-[2-(acetylamino)-1,3-thiazol-4-yl]phenylsulfinate (731 mg) as acolorless solid.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 7.52(2H, d, J=8.0 Hz), 7.54(1H,s), 7.84(2H, d, J=8.0 Hz).

MS: 281(M−H)⁺ free

Step 7

Sodium 4-[2-(acetylamino)-1,3-thiazol-4-yl]phenylsulfinate (600 mg) wasdissolved in DMF (2 ml) under N₂ atmosphere. Then 2-bromoethanol (0.168ml) was added to the solution at 0° C. The reaction mixture was stirredat 100° C. for 7 hours. After cooled to r.t., water and AcOEt were addedto the mixture. The precipitate was filtered in vacuo to giveN-(4-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-1,3-thiazol-2-yl)acetamide(80.2 mg) as an off-white solid.

mp. 258–260° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.18(3H, S), 3.47(2H, t, J=6.0 Hz), 3.70(2H,q, J=6.0 Hz), 4.89(1H, t, J=6.0 Hz), 7.89(1H, s), 7.94(2H, d, J=8.5 Hz),8.13(2H, d, J=8.5 Hz), 12.36(1H, brs).

MS: 325(M−H)⁺

Step 8

N-(4-{4-[(2-Hydroxyethyl)sulfonyl]phenyl}-1,3-thiazol-2-yl)acetamide(200 mg), Et₃N (0.102 ml) and CH₂Cl₂ (4 ml) were combined under N₂atmosphere, and then MsCl (0.05 ml) was added to the suspension at 0° C.The reaction mixture was stirred at r.t. for 2 hours. MeOH/CHCl₃ andwater were added to the mixture, and the mixture was extracted. Theorganic layer was washed with brine, dried over anhydrous MgSO₄, andconcentrated in vacuo. The residual solid (221.6 mg) was suspended inCH₃CN (10 ml), and then 28% ammonia solution (0.5 ml) was added to thesuspension at 0° C. The reaction mixture was stirred at r.t. for 15hours, and concentrated in vacuo. The residue was purified by flashcolumn chromatography over silica gel with [MeOH/CHCl₃ (1:30), thenNH₄OH/MeOH/CHCl₃ (1:10:60)] as an eluent, and triturated with EtOH/ethylether to giveN-(4-{4-[(2-aminoethyl)sulfonyl]phenyl}-1,3-thiazol-2-yl)acetamide (60.4mg) as an off-white solid.

mp. 287–288° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.18(3H, s), 2.79(2H, t, J=6.5 Hz), 3.36(2H,q, J=6.5 Hz), 7.90(1H, s), 7.94(2H, d, J=8.5 Hz), 8.15(2H, d, J=8.5 Hz).

MS: 326(M+H)⁺

Step 9

Di-tert-butyl((Z)-{[2-({4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}sulfonyl)ethyl]amino}methylidene)biscarbamatewas prepared from the compound of Step 8 in a similar manner accordingto Step 3 of Production Example 31.

mp. 280–281° C.

¹H-NMR (DMSO-d₆), δ (ppm): 1.38(9H, s), 1.39(9H, s), 2.18(3H, s),3.65(4H, s), 7.88(1H, s), 7.93(2H, d, J=8.5 Hz), 8.13(2H, d, J=8.5 Hz),8.32(1H, brs), 11.32(1H, brs), 12.35(1H, brs).

MS: 568(M+H)⁺

Step 10

The title compound was prepared from the compound of Step 9 in a similarmanner according to Step 4 of Production Example 31.

mp. 188–189.5° C.

¹H-NMR (DMSO-d₆), δ (ppm): 2.18(3H, s), 3.51(2H, m), 3.59(2H, t, J=6.0Hz), 7.28(3H, brs), 7.62(1H, t, J=5.5 Hz), 7.93(1H, s), 7.98(2H, d,J=8.5 Hz), 8.17(2H, d, J=8.5 Hz), 12.37(1H, brs).

MS: 368(M+H)^(+ free)

PRODUCTION EXAMPLE 112 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[3-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamidehydrochloride

Step 1

N-Methoxy-N-methyl-3-(methylsulfonyl)benzamide was prepared from3-(methylsulfonyl)benzoic acid in a similar manner according to Step 1of Production Example 31.

¹H-NMR (CDCl₃), δ (ppm): 3.08(3H, s), 3.40(3H, s), 3.55(3H, s), 7.64(1H,t, J=8.0 Hz), 7.99(1H, dt, J=8.0, 1.5 Hz), 8.03(1H, dt, J=8.0, 1.5 Hz),8.28(1H, t, J=1.5 Hz).

MS: 244(M+H)⁺

Step 2

To a stirred solution of N-methoxy-N-methyl-3-(methylsulfonyl)benzamide(5 g) in dry THF (100 ml) was added dropwise DIBALH (22.6 ml) at −78° C.under N₂ atmosphere. The action mixture was stirred for 4 hours at r.t.and then quenched with MeOH at 0° C. AcOEt and 1N—HCl were added to themixture, and extracted. The organic layer was washed with brine, driedover anhydrous MgSO₄, and concentrated in vacuo. The residual oil (3.38g), methyl (triphenylphosphoranylidene)acetate (6.87 g) and THF (68 ml)were combined at r.t. under N₂ atmosphere, and the reaction mixture wasrefluxed for 3 hours. The solvent was removed in vacuo, and the residuewas suspended in AcOEt. The solid was filtered off, and the filtrate wasconcentrated in vacuo. The residue was purified by flash columnchromatography over silica gel with n-hexane/AcOEt (2:1) as an eluent togive methyl (2E)-3-[3-(methylsulfonyl)phenyl]acrylate (613.8 mg) asyellow oil.

¹H-NMR (DMSO-d₆), δ (ppm): 3.28(3H, s), 3.75(3H, s), 6.85(1H, d, J=16.0Hz), 7.74(1H, s), 7.93(1H, t, J=8.0 Hz), 7.96(1H, d, J=8.0 Hz), 8.09(1H,d, J=8.0 Hz), 8.32(1H, d, J=16.0 Hz).

Step 3

Methyl (2E)-3-[3-(methylsulfonyl)phenyl]acrylate (600 mg), MeOH (6.ml)and then 10% palladium carbon (99.9 mg) were combined under N₂atmosphere. The reaction mixture was stirred at r.t. for 7 hours underH₂ atmosphere (1 atm), and filtered through a celite pad. The filtratewas concentrated in vacuo. The residue was purified by flash columnchromatography over silica gel with n-hexane/AcOEt (1:1→1:2) as aneluent to give methyl 3-[3-(methylsulfonyl)phenyl]propanoate (283.3 mg)as colorless oil.

¹H-NMR (DMSO-d₆), δ (ppm): 2.70(2H, t, J=7.5 Hz), 2.97(2H, t, J=7.5 Hz),3.20(3H, s), 3.58(3H, s), 7.52–7.63(2H, m), 7.73–7.80(2H, m).

Step 4

Ethyl 4-[3-(methylsulfonyl)phenyl]-2-oxobutanoate was prepared from thecompound of Step 3 in a similar manner according to Step 2 of ProductionExample 47.

¹H-NMR (CDCl₃), δ (ppm): 1.35(3H, t, J=7.0 Hz), 3.05(2H, t, J=7.0 Hz),3.06(3H, s), 3.24(2H, t, J=7.0 Hz), 4.32(2H, q, J=7.0 Hz), 7.45–7.82(4H,m).

Step 5

Ethyl 3-bromo-4-[3-(methylsulfonyl)phenyl]-2-oxobutanoate was preparedfrom the compound of Step 4 in a similar manner according to Step 1-ofProduction Example 46.

¹H-NMR (CDCl₃), δ (ppm): 1.37(3H, t, J=7.0 Hz), 3.07(3H, s), 3.34(1H,dd, J=14.5, 8.0 Hz), 3.60(1H, dd, J=14.5, 6.5 Hz), 4.35(2H, q, J=7.0Hz), 5.26(1H, dd, J=8.0, 6.5 Hz), 7.49–7.88(4H, m).

Step 6

Ethyl 2-amino-5-[3-(methylsulfonyl)benzyl]-1,3-thiazole-4-carboxylatewas prepared from the compound of Step 5 in a similar manner accordingto Step 2 of Production Example 46.

¹H-NMR (DMSO-d₆), δ (ppm): 1.24(3H, t, J=7.0 Hz), 3.20(3H, s), 4.20(2H,q, J=7.0 Hz), 4.46(2H, s), 7.10(2H, s), 7.57–7.61(2H, m), 7.76–7.83(2H,m).

MS: 341(M+H)⁺

Step 7

Ethyl2-(acetylamino)-5-[3-(methylsulfonyl)benzyl]-1,3-thiazole-4-carboxylatewas prepared from the compound of Step 6 in a similar manner accordingto Step 3 of Production Example 45.

¹H-NMR (DMSO-d₆), δ (ppm): 1.27(3H, t, J=7.0 Hz), 2.10(3H, s), 3.20(3H,s), 4.27(2H, q, J=7.0 Hz), 4.61(2H, s), 7.56–7.66(2H, m), 7.77–7.89(2H,m), 12.47(1H, s).

MS: 383(M+H)⁺

Step 8

Ethyl²-(acetylamino)-5-[3-(methylsulfonyl)benzyl]-1,3-thiazole-4-carboxylate(54.7 mg) was suspended in THF (1 ml) under N₂ atmosphere, and thenlithium aluminium hydride (7.79 mg) was added portionwise to thesuspension at 0° C. The reaction mixture was refluxed for 2.5 hours, andquenched with MeOH and 1N—HCl at 0° C. Anhydrous MgSO₄ was added to themixture, and stirred at r.t. for 1 hour. The suspension was filtered invacuo. The filtrate was concentrated in vacuo.

The residual oil (114.8 mg), CHCl₃ (1 ml), CH₃CN (1 ml) and Dess-Martinperiodinane (88 mg) were combined at 0° C. under N₂ atmosphere. Thereaction mixture was stirred at r.t. for 1 hour, and diluted in CHCl₃.The organic solution was washed with saturated NaHCO₃, water and brine,dried over anhydrous MgSO₄, and concentrated in vacuo to giveN-{4-formyl-5-[3-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(61.2 mg) as a yellow amorphous.

¹H-NMR (DMSO-d₆), δ (ppm): 2.13(3H, s), 3.17(3H, s), 4.67(2H, s),7.56–7.90(4H, m), 10.04(1H, s), 12.39(1H, s).

Step 9

N-{5-[3-(Methylsulfonyl)benzyl]-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamidewas prepared from the compound of Step 8 in a similar manner accordingto Step 5 of Production Example 45.

¹H-NMR (DMSO-d₆), δ (ppm): 2.08(3H×⅔, s), 2.13(3H×⅓, s), 3.18(3H, s),4.23(2H×⅔, s), 4.50(2H×⅓, s), 6.69–8.31(10H, m).

Step 10

N-{4-[2-(4-Aminophenyl)ethyl]-5-[3-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamidewas prepared from the compound of Step 9 in a similar manner accordingto Step 6 of Production Example 45.

MS: 430(M+H)⁺

Step 11

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[3-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from the compound of Step 10 in a similar manner accordingto Step 3 of Production Example 31.

¹H-NMR [CD₃Cl/CD₃OD (1:1)], δ (ppm): 1.29(9H, s), 1.55(9H, s), 2.23(3H,s), 2.89(4H, m), 3.07(3H, s), 3.90(2H, s), 7.11–7.87(8H, m).

MS: 672(M+H)⁺

Step 12

The title compound was prepared from the compound of Step 11 in asimilar manner according to Step 4 of Production Example 31.

¹H-NMR (CD₃OD), δ (ppm): 2.08(3H, s), 2.98(4H, m), 3.10(3H, s), 3.98(2H,s), 7.10–7.88(8H, m).

MS: 472(M+H)^(+ free)

PRODUCTION EXAMPLE 113 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[(1,1-dioxido-4-thiomorpholinyl)methyl]-1,3-thiazol-2-yl}acetamidedihydrochloride

Step 1

N-{5-[(1,1-Dioxido-4-thiomorpholinyl)methyl]-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamidewas prepared fromN-{4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide in asimilar manner according to Step 1 of Production Example 67.

MS: 437.12(M+H)⁺

Step 2

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[(1,1-dioxido-4-thiomorpholinyl)methyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from the compound of Step 1 in a similar manner accordingto Step 2 of Production Example 68.

¹H-NMR (CDCl₃), δ (ppm): 1.49(9H, s), 1.53(9H, s), 2.23(3H, s),2.70–2.95(8H, m), 2.95–3.12(4H, s), 3.45(2H, s), 6.99(2H, d, J=8.3 Hz),7.42(2H, d, J=8.3 Hz), 8.94–9.24(1H, brs), 10.24(1H, s), 11.63(1H, s).

MS: 651.1(M+H)⁺, 673.3(M+Na)⁺

Step 3

The title compound was prepared from the compound of Step 2 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.15(3H, s), 2.97(4H, s), 3.77–4.63(8H, s),4.45(2H, s), 7.15(2H, d, J=8.3 Hz), 7.32(2H, d, J=8.3 Hz), 7.46(4H, s),9.96(1H, s), 12.29(1H, s).

MS: 451.3(M+H)⁺, 473.2(M+Na)⁺

PRODUCTION EXAMPLE 114 Synthesis ofN-[4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-(4-morpholinylmethyl)-1,3-thiazol-2-yl]acetamidedihydrochloride

Step 1

N-{5-(4-Morpholinylmethyl)-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamidewas prepared fromN-{4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide in asimilar manner according to Step 1 of Production Example 67.

MS: 389.16(M+H)⁺

Step 2

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-(4-morpholinylmethyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound of Step 1 in a similar manner accordingto Step 2 of Production Example 68.

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.53(9H, s), 2.22(3H, s),2.30–2.46(4H, m), 2.85(4H, s), 3.39(2H, s), 3.58–3.75(4H, m), 7.07(2H,d, J=8.4 Hz), 7.45(2H, d, J=8.4 Hz), 8.80–9.31(1H, brs), 10.24(1H, s),11.63(1H, s).

MS: 603.3(M+H)⁺

Step 3

The title compound was prepared from the compound of Step 2 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR(DMSO-d₆), δ (ppm): 2.16(3H, s), 2.97(4H, s), 3.00–3.12(2H, m),3.16–3.27(2H, m), 3.65–3.76(2H, m), 3.86–3.97(2H, m), 4.43(2H, s),7.15(2H, d, J=8.4 Hz), 7.31(2H, d, J=8.4 Hz), 7.40(4H, s), 9.86(1H, s),10.54–10.84(1H, brs), 12.34(1H, s).

MS: 403.1(M+H)⁺, 426.1(M+Na)⁺

PRODUCTION EXAMPLE 115 Synthesis ofN-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[(3-oxo-1-piperazinyl)methyl]-1,3-thiazol-2-yl}acetamidedihydrochloride

Step 1

N-{4-[(Z)-2-(4-Nitrophenyl)vinyl]-5-[(3-oxo-1-piperazinyl)methyl]-1,3-thiazol-2-yl}acetamidewas prepared fromN-{4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide in asimilar manner according to Step 1 of Production Example 67.

Z:E=3:1

¹H-NMR (DMSO-d₆), δ (ppm): 2.10(3H×¾, s), 2.15(3H×¼, s), 2.54–2.59(2H×¾,m), 2.61–2.67(2H×¼, m), 2.93(2H×¾, s), 3.02(2H×¼, m), 3.08–3.19(2H, m),3.64(2H×¾, s), 3.95(2H×¼, s), 6.72(1H×¾, d, J=12.4 Hz), 6.78(1H×¾, d,J=12.4 Hz), 7.34(1H×¼, d, J=15.7 Hz), 7.59(1×¼, d, J=15.7 Hz),7.62(2H×¾, d, J=8.8 Hz), 7.76(1H×¾, s), 7.78(1H×¼, s), 7.90(2H×¼, d,J=8.8 Hz), 8.14(2H×¾, d, J=8.8 Hz), 8.21(2H×¼, d, J=8.8 Hz),11.75–12.06(1H×¾, brs), 12.08–12.33(1H×¼, brs).

MS: 402.21(M+H)⁺

Step 2

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[(3-oxo-1-piperazinyl)methyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from the compound of Step 1 in a similar manner accordingto Step 2 of Production Example 68.

¹H-NMR (CDCl₃), δ (ppm): 1.49(9H, s), 1.53(9H, s), 2.24(3H, s),2.47–2.55(2H, m), 2.80–2.93(4H, m), 3.13(2H, s), 3.24–3.32(2H, m),3.43(2H, s), 6.02(1H, s), 7.04(2H, d, J=8.4 Hz), 7.44(2H, d, J=8.3 Hz),9.02–9.26(1H, brs), 10.24(1H, s), 11.62(1H, s).

MS: 616.2(M+H)⁺, 638.2(M+Na)⁺

Step 3

The title compound was prepared from the compound of Step 2 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.15(3H, s), 2.39–2.62(2H, m), 2.95(4H, s),3.08–3.86(4H, m), 4.20–4.77(2H, brs), 7.15(2H, d, J=8.3 Hz), 7.30(2H, d,J=8.0 Hz), 7.35(4H, s), 8.04–8.62(1H, brs), 9.70(1H, s), 10.67–11.38(1H,brs), 11.97–12.72(1H, brs).

MS: 416.2(M+H)^(+ free)

PRODUCTION EXAMPLE 116 Synthesis of4-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)-N,N-dimethyl-1-piperazinecarboxamidedihydrochloride

Step 1

9H-Fluoren-9-ylmethyl4-({2-(acetylamino)-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-5-yl}methyl)-1-piperazinecarboxylatewas prepared fromN-{4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide in asimilar manner according to Step 1 of Production Example 67.

¹H-NMR (CDCl₃), δ (ppm): 2.10(3H, s), 2.26–2.61(4H, m), 3.39–3.64(6H,m), 4.19–4.30(1H, m), 4.37–4.49(2H, m), 6.66(2H, s), 7.07–7.67(8H, m),7.76(2H, d, J=6.9 Hz), 8.05(2H, d, J=8.9 Hz), 10.03(1H, s).

MS: 610.2(M+H)⁺, 632.2(M+Na)⁺

Step 2

9H-Fluoren-9-ylmethyl4-({2-(acetylamino)-4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-5-yl}methyl)-1-piperazinecarboxylate was prepared from the compound of Step1 in a similar manner according to Step 6 of Production Example 45.

¹H-NMR (CDCl₃), δ (ppm): 2.16–2.33(7H, m), 2.80(4H, s), 3.34(2H, s),3.36–3.84(6H, m), 4.17–4.30(1H, m), 4.36–4.47(2H, m), 6.57(2H, d, J=8.4Hz), 6.86(2H, d, J=8.3 Hz), 7.26–7.46(4H, m), 7.56(2H, d, J=7.0 Hz),7.76(2H, d, J=6.9 Hz), 8.60–9.52(1H, brs).

MS: 582.2(M+H)⁺, 604.3(M+Na)⁺

Step 3

9H-Fluoren-9-ylmethyl4-[(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)methyl]-1-piperazinecarboxylatewas prepared from the compound of Step 2 in a similar manner accordingto Step 3 of Production Example 31.

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.52(9H, s), 2.23(3H, s),2.28–2.43(4H, m), 2.86(4H, s), 3.36–3.55(6H, m), 4.18–4.29(1H, m),4.35–4.48(2H, m), 7.05(2H, d, J=8.5 Hz), 7.13–7.66(8H, m), 7.75(2H, d,J=7.0 Hz), 8.85–9.76(1H, brs), 10.25(1H, Ss), 11.63(1H, s).

MS: 824.2(M+H)⁺, 847.3(M+Na)⁺

Step 4

To a solution of 9H-fluoren-9-ylmethyl4-[(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)methyl]-1-piperazinecarboxylate(400 mg) in DMF (0.8 ml) was added piperidine (0.16 ml), and the mixturewas stirred for 2 h at 20° C. To the reaction mixture was addedpiperidine (0.16 ml), stirred at 20° C. for 1 h and 40° C. for 1 h, thencooled to 20° C., added AcOEt (50 ml), and the mixture was washed withwater (10 ml×3) and brine (10 ml), dried over MgSO₄, filtered andconcentrated in vacuo to give crude pale yellow oil (463 mg). The crudeoil was purified by flash column chromatography over NH silica gel withdichloromethane/methanol (100:0)→(100:1) as an eluent to givedi-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-(1-piperazinylmethyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamateas a colorless amorphous.

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.53(9H, s), 2.21(3H, s),2.27–2.47(4H, m), 2.71–3.00(8H, m), 3.40(2H, s), 7.07(2H, d, J=8.4 Hz),7.45(2H, d, J=8.4 Hz), 10.24(1H, s), 11.47–11.74(1H, brs).

MS: 602.3(M+H)⁺, 624.2(M+Na)⁺

Step 5

To a solution of di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-(1-piperazinylmethyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate(30 mg) in dichloromethane (0.3 ml) were added N,N-diisopropylethylamine(9.55 μl) and dimethylcarbamyl chloride (4.59 μl), and the mixture wasstirred for 14 h at 20° C. To the reaction mixture was added saturatedsodium hydrogen carbonate aqueous solution (2 ml), then the mixture wasextracted with diclhloromethane (5 ml×3) and the extract was dried overdiatomaceous earth. The organic layer was concentrated in vacuo to givecrude oil. The residue was purified by preparative silica gel thin-layerchromatography with chloroform/methanol (20:1) as an eluent to givedi-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({4-[(dimethylamino)carbonyl]-1-piperazinyl}methyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate ascolorless oil.

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.54(9H, s), 2.23(3H, s),2.35–2.42(4H, m), 2.80(6H, s), 2.81–2.89(4H, m), 3.17–3.27(4H, m),3.41(2H, s), 7.07(2H, d, J=8.4 Hz), 7.46(2H, d, J=8.4 Hz), 8.73–8.90(1H,brs), 10.25(1H, s), 11.63(1H, s).

MS: 673.3(M+H)⁺, 695.2(M+Na)⁺

Step 6

The title compound was prepared from the compound of Step 5 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR(DMSO-d₆), δ (ppm): 2.16(3H, s), 2.76(6H, s), 2.91–3.06(6H, m),3.07–3.19(2H, m), 3.20–3.30(2H, m), 3.57–3.65(2H, m), 4.36–4.51(2H, m),7.15(2H, d, J=8.4 Hz), 7.31(2H, d, J=8.4 Hz), 7.41(4H, s), 9.87(1H, s),10.51–10.69(1H, brs), 12.33(1H, s).

MS: 473.2(M+H)⁺

PRODUCTION EXAMPLE 117 Synthesis ofN-(4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-{[4-(4-morpholinylcarbonyl)-1-piperazinyl]methyl}-1,3-thiazol-2-yl)acetamide dihydrochloride

Step 1

Di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{[4-(4-morpholinylcarbonyl)-1-piperazinyl]methyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared from the compound of Step 4 of Production Example 116 in asimilar manner according to Step 5 of Production Example 116.

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.54(9H, s), 2.23(3H, s),2.32–2.46(4H, m), 2.78–2.91(4H, m), 3.20–3.30(8H, m), 3.42(2H, s),3.63–3.71(4H, m), 7.07(2H, d, J=8.4 Hz), 7.46(2H, d, J=8.4 Hz),8.72–8.89(1H, brs), 10.25(1H, s), 11.64(1H, s).

MS: 715.3(M+H)⁺, 737.2(M+Na)⁺

Step 2

The title compound was prepared from the compound of Step 1 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 2.90–3.07(6H, m), 3.11–3.32(8H,m), 3.48–3.76(6H, m), 4.42(2H, s), 7.15(2H, d, J=8.4 Hz), 7.31(2H, d,J=8.4 Hz), 7.40(4H, s), 9.85(1H, s), 10.51–10.72(1H, brs), 12.34(1H, s).

MS: 515.3(M+H)^(+ free)

PRODUCTION EXAMPLE 118 Synthesis ofN-(4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-{[4-(1-pyrrolidinylcarbonyl)-1-piperazinyl]methyl}-1,3-thiazol-2-yl)acetamidedihydrochloride

Step 1

Di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{[4-(1-pyrrolidinylcarbonyl)-1-piperazinyl]methyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared from the compound of Step 4 of Production Example 116 in asimilar manner according to Step 5 of Production Example 116.

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.54(9H, s), 1.72–1.89(4H, m),2.23(3H, s), 2.28–2.48(4H, m), 2.84(4H, s), 3.19–3.39(8H, m), 3.41(2H,s), 7.07(2H, d, J=8.4 Hz), 7.46(2H, d, J=8.4 Hz), 8.71–8.99(1H, brs),10.24(1H, s), 11.64(1H, s).

MS: 699.2(M+H)⁺, 721.3(M+Na)⁺

Step 2

The title compound was prepared from the compound of Step 1 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.70–1.83(4H, m), 2.16(3H, s), 2.89–3.05(6H,m), 3.06–3.19(2H, m), 3.20–3.32(6H, m), 3.64–3.84(2H, m), 4.36–4.50(2H,m), 7.15(2H, d, J=8.2 Hz), 7.31(2H, d, J=8.3 Hz), 7.42(4H, s), 9.88(1H,s), 10.50–10.75(1H, brs), 12.34(1H, s).

MS: 499.3(M+H)^(+ free)

PRODUCTION EXAMPLE 119 Synthesis ofN-[4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-({4-[(4-methyl-1-piperazinyl)carbonyl]-1-piperazinyl}methyl)-1,3-thiazol-2-yl]acetamidetrihydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({4-[(4-methyl-1-piperazinyl)carbonyl]-1-piperazinyl}methyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound of Step 4 of Production Example 116 in asimilar manner according to Step 5 of Production Example 116.

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.54(9H, s), 2.23(3H, s), 2.29(3H,s), 2.32–2.48(8H, m), 2.84(4H, s), 3.16–3.35(8H, m), 3.42(2H, s),7.07(2H, d, J=8.4 Hz), 7.46(2H, d, J=8.4 Hz), 8.69–9.04(1H, brs),10.24(1H, s), 11.64(1H, s).

MS: 728.2(M+H)⁺, 750.3(M+Na)⁺

Step 2

The title compound was prepared from the compound of Step 1 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.16(3H, s), 2.76(3H, d, J=4.6 Hz),2.89–3.09(8H, m), 3.17–3.39(8H, m), 3.62–3.77(4H, m), 4.34–4.51(2H,brs), 7.15(2H, d, J=8.3 Hz), 7.31(2H, d, J=8.2 Hz), 7.41(4H, s),9.87(1H, s), 10.68–10.97(1H, brs), 12.34(1H, s).

MS: 528.3(M+H)^(+ free)

PRODUCTION EXAMPLE 120 Synthesis of3-{2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}-N,N-dimethylpropanamidehydrochloride

Step 1

Ethyl3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]acrylatewas prepared from2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carbaldehydein a similar manner according to Step 7 of Production Example 61.

¹H-NMR (CDCl₃), δ (ppm): 1.16–1.40(3H, m), 1.52(9H, s), 2.23–2.38(3H,m), 2.70–3.06(4H, m), 4.15–4.33(2H, m), 5.53–6.15(1H, m), 6.64–7.85(6H,m).

MS: 482.2(M+Na)⁺

Step 2

A mixture of ethyl(2E)-3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]acrylateand ethyl(2Z)-3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]acrylate(200 mg), THF (7 ml) and 10% Pd/C (392 mg) were combined under nitrogenatmosphere. The mixture was stirred under 3 atm hydrogen atmosphere at20° C. for 3 h. The reaction mixture was filtered through a celite pad,and the filtrate was concentrated in vacuo to give ethyl3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]propanoateas a colorless amorphous.

¹H-NMR (CDCl₃), δ (ppm): 1.24(3H, t, J=7.0 Hz), 1.51(9H, s), 2.24(3H,s), 2.41(2H, t, J=7.5 Hz), 2.73–2.93(6H, m), 4.12(2H, q, J=7.0 Hz),6.95(2H, d, J=7.2 Hz), 7.23(2H, d, J=7.7 Hz).

MS: 484.1(M+Na)⁺

Step 3

Ethyl3-(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)propanoatewas prepared from the compound of Step 2 in a similar manner accordingto Step 4 of Production Example 65.

¹H-NMR (CDCl₃), δ (ppm): 1.24(3H, t, J=7.1 Hz), 1.50(9H, s), 1.53(9H,s), 2.21(3H, s), 2.41(2H, t, J=7.6 Hz), 2.70–3.00(6H, m), 4.12(2H, q,J=7.2 Hz), 7.07(2H, d, J=8.4 Hz), 7.46(2H, d, J=8.4 Hz), 8.80–9.20(1H,brs), 10.24(1H, s), 11.63(1H, s).

MS: 604.3(M+H)⁺, 626.2(M+Na)⁺

Step 4

3-(2-(Acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)propanoicacid was prepared from the compound of Step 3 in a similar manneraccording to Step 1 of Production Example 42.

¹H-NMR (CDCl₃), δ (ppm): 1.47(9H, s), 1.53(9H, s), 2.19(3H, s),2.25–2.45(2H, m), 2.60–3.00(6H, m), 6.96(2H, d, J=8.3 Hz), 7.34(2H, d,J=8.3 Hz), 10.17(1H, s), 11.30–11.90(1H, brs).

MS: 598.2(M+Na)⁺

Step 5

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[3-(dimethylamino)-3-oxopropyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from the compound of Step 4 in a similar manner accordingto Step 1 of Production Example 32.

¹H-NMR (CDCl₃), δ (ppm): 1.49(9H, s), 1.53(9H, s), 2.21(3H, s),2.28–2.43(2H, m), 2.79–2.99(12H, m), 7.05(2H, d, J=8.5 Hz), 7.44(2H, d,J=8.5 Hz), 8.85–9.37(1H, brs), 10.23(1H, s), 11.62(1H, s).

MS: 603.3(M+H)⁺, 625.3(M+Na)⁺

Step 6

The title compound was prepared from the compound of Step 5 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.10(3H, s), 2.40(2H, t, J=7.3 Hz), 2.75(2H,t, J=7.3 Hz), 2.77–2.84(5H, m), 2.84–2.95(5H, m), 7.14(2H, d, J=8.4 Hz),7.24(2H, d, J=8.4 Hz), 7.36(4H, s), 9.72(1H, s), 11.93(1H, s).

MS: 403.3(M+H)^(+ free)

PRODUCTION EXAMPLE 121 Synthesis of3-{2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}-N-methylpropanamidehydrochloride

Step 1

Di-tert-butyl((Z)-{[4-(2-{2-(acetylamino)-5-[3-(methylamino)-3-oxopropyl]-1,3-thiazol-4-yl}ethyl)phenyl]amino}methylidene)biscarbamatewas prepared from the compound of Step 4 of Production Example 120 in asimilar manner according to Step 1 of Production Example 32.

¹H-NMR (CDCl₃), δ (ppm): 1.45(9H, s), 1.54(9H, s), 1.79–1.88(2H, s),2.23(3H, s), 2.65(3H, d, J=4.8 Hz), 2.69–2.77(2H, m), 2.79–2.86(2H, m),2.86–2.95(2H, m), 6.04(2H, d, J=4.4 Hz), 6.93(2H, d, J=8.4 Hz), 7.28(2H,d, J=8.4 Hz), 8.79–9.17(1H, brs), 10.28(1H, s), 11.60(1H, s).

MS: 589.3(M+H)⁺, 611.3(M+Na)⁺

Step 2

The title compound was prepared from the compound of Step 1 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.10(3H, s), 2.22(2H, t, J=7.3 Hz), 2.53(3H,d, J=4.8 Hz), 2.72–2.82(4H, m), 2.82–2.90(2H, m), 7.15(2H, d, J=8.4 Hz),7.26(2H, d, J=8.4 Hz), 7.38(4H, s), 7.79(1H, d, J=4.5 Hz), 9.76(1H, s),11.95(1H, s).

MS: 389.2(M+H)⁺, 411.2(M+Na)^(+ free)

PRODUCTION EXAMPLE 122 Synthesis of3-{2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}propanamidehydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-(3-amino-3-oxopropyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound of Step 4 of Production Example 120 in asimilar manner according to Step 1 of Production Example 32.

¹H-NMR (CDCl₃), δ (ppm): 1.47(9H, s), 1.53(9H, s), 1.57–1.67(2H, m),2.24(3H, s), 2.65–2.76(2H, m), 2.76–2.87(2H, m), 2.87–2.99(2H, m),5.37(1H, s), 6.14(1H, s), 6.90(2H, d, J=8.4 Hz), 7.28(2H, d, J=8.4 Hz),8.88–9.28(1H, brs), 10.12(1H, s), 11.58(1H, s).

MS: 575.0(M+H)⁺, 597.3(M+Na)⁺

Step 2

The title compound was prepared from the compound of Step 1 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 2.10(3H, s), 2.23(2H, t, J=7.3 Hz),2.71–2.83(4H, m), 2.83–2.91(2H, m), 6.81(1H, s), 7.14(2H, d, J=8.4 Hz),7.26(2H, d, J=8.4 Hz), 7.31(1H, s), 7.35(4H, s), 9.70(1H, s), 11.94(1H,s).

MS: 375.2(M+H)⁺, 397.0(M+Na)^(+ free)

PRODUCTION EXAMPLE 123 Synthesis of1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)-N,N-dimethyl-4-piperidinecarboxamidedihydrochloride

Step 1

1-[(2-(Acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)methyl]-4-piperidinecarboxylicacid was prepared from ethyl1-[(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)methyl]-4-piperidinecarboxylatein a similar manner according to Step 1 of Production Example 42.

¹H-NMR (CDCl₃), δ (ppm): 1.49(9H, s), 1.51(9H, s), 1.76–2.49(10H, m),2.69–3.00(6H, m), 3.71(2H, s), 7.04(2H, d, J=8.5 Hz), 7.42(2H, d, J=8.5Hz), 10.23(1H, s), 11.13–12.07(1H, brs).

MS: 645.3(M+H)⁺, 667.2(M+Na)⁺

Step 2

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({4-[(dimethylamino)carbonyl]-1-piperidinyl}methyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound of Step 1 in a similar manner accordingto Step 1 of Production Example 32.

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.54(9H, s), 1.75–1.89(2H, m),1.92–2.03(2H, m), 2.22(3H, s), 2.37–2.49(1H, m), 2.80–2.95(9H, m),3.02(3H, s), 3.43(2H, s), 7.08(2H, d, J=8.4 Hz), 7.46(2H, d, J=8.4 Hz),8.61–9.19(1H, brs), 10.24(1H, s), 11.63(1H, s).

MS: 672.2(M+H)⁺, 694.3(M+Na)⁺

Step 3

The title compound was prepared from the compound of Step 2 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.71–2.01(4H, m), 2.16(3H, s), 2.76–2.87(4H,m), 2.87–3.1(9H, m), 3.3–3.4(2H, m), 4.32–4.45(2H, m), 7.15(2H, d, J=4.2Hz), 7.31(2H, d, J=4.2 Hz), 7.41(4H, s), 9.83–9.93(1H, m),9.99–10.19(1H, m), 12.32–12.37(1H, m).

MS: 472.3(M+H)⁺, 494.0(M+Na)^(+ free)

PRODUCTION EXAMPLE 124 Synthesis of1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)-N-methyl-4-piperidinecarboxamidedihydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({4-[(methylamino)carbonyl]-1-piperidinyl}methyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound of Step 1 of Production Example 123 in asimilar manner according to Step 1 of Production Example 32.

¹H-NMR (CDCl₃), δ (ppm): 1.5(9H, s), 1.54(9H, s), 1.65–1.74(2H, m),1.75–1.84(2H, m), 1.87–1.98(2H, m), 2–2.11(1H, m), 2.22(3H, s), 2.8(3H,d, J=4.8 Hz), 2.82–2.91(6H, m), 3.39(2H, s), 5.5(1H, d, J=4.4 Hz),7.07(2H, d, J=8.4 Hz), 7.45(2H, d, J=8.4 Hz), 8.72–8.99(1H, brs),10.23(1H, s), 11.62(1H, s).

MS: 658.3(M+H)⁺, 680.3(M+Na)⁺

Step 2

The title compound was prepared from the compound of Step 1 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.71–2.04(4H, m), 2.16(3H, s), 2.25–2.37(1H,m), 2.54–2.61(3H, m), 2.82–2.94(2H, m), 2.96(4H, s), 3.27–3.37(2H, m),4.31–4.44(2H, m), 7.15(2H, d, J=8.4 Hz), 7.30(2H, d, J=8.4 Hz), 7.41(4H,s), 7.89–8.00(1H, m), 9.83–10.16(2H, m).

MS: 458.2(M+H)⁺, 480.0(M+Na)⁺ free

PRODUCTION EXAMPLE 125 Synthesis of1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)-4-piperidinecarboxamidedihydrochloride

Step 1

Di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{[4-(aminocarbonyl)-1-piperidinyl]methyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared from the compound of Step 1 of Production Example 123 in asimilar manner according to Step 1 of Production Example 32.

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.53(9H, s), 1.66–1.75 (2H, m),1.78–1.87(2H, m), 1.88–1.99(2H, m), 2.07–2.17(1H, m), 2.23(3H, s),2.77–2.92(6H, m), 3.39(2H, s), 5.5(2H, s), 7.06(2H, d, J=8.4 Hz),7.45(2H, d, J=8.4 Hz), 8.94–9.25(1H, brs), 10.23(1H, s), 11.61(1H, s).

MS: 644.2(M+H)⁺, 666.3(M+Na)⁺

Step 2

The title compound was prepared from the compound of Step 1 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.68–2.08(4H, m), 2.16(3H, s), 2.25–2.36(1H,m), 2.82–3.09(6H, m), 3.27–3.44(2H, m), 4.30–4.45 (2H, m), 6.87–7.06(1H,m), 7.15(2H, d, J=8.4 Hz), 7.30(2H, d, J=8.3 Hz), 7.36–7.52(5H, m),9.87–10.25(2H, m), 12.30–12.37(1H, m).

MS: 444.2(M+H)⁺, 466.2(M+Na)^(+ free)

PRODUCTION EXAMPLE 126 Synthesis of(3R)-1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)-N,N-dimethyl-3-piperidinecarboxamidedihydrochloride

Step 1

Ethyl(3R)-1-({2-(acetylamino)-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-5-yl}methyl)-3-piperidinecarboxylatewas prepared fromN-{4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide in asimilar manner according to Step 1 of Production Example 67.

MS: 459.20(M+H)⁺

Step 2

Ethyl(3R)-1-[(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)methyl]-3-piperidinecarboxylatewas prepared from the compound of Step 1 in a similar manner accordingto Step 2 of Production Example 68.

¹H-NMR (CDCl₃), δ (ppm): 1.22(3H, t, J=7.2 Hz), 1.31–1.78(21H, m),1.79–2.06(2H, m), 2.07–2.18(1H, m), 2.22(3H, s), 2.43–2.62(1H, m),2.62–2.75(1H, m), 2.84(4H, s), 2.88–3.01(1H, m), 3.42(2H, s), 4.11(2H,q, J=7.1 Hz), 7.08(2H, d, J=8.4 Hz), 7.46(2H, d, J=8.4 Hz),8.76–9.16(1H, brs), 10.24(1H, s), 11.64(1H, s).

MS: 673.3(M+H)⁺, 695.2(M+Na)⁺

Step 3

(3R)-1-[(2-(Acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)methyl]-3-piperidinecarboxylicacid was prepared from the compound of Step 2 in a similar manneraccording to Step 1 of Production Example 42.

MS: 645.37(M+H)⁺

Step 4

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({(3R)-3-[(dimethylamino)carbonyl]-1-piperidinyl}methyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound of Step 3 in a similar manner accordingto Step 1 of Production Example 32.

¹H-NMR (CDCl₃), δ (ppm): 1.39–1.57(20H, m), 1.66–1.73(1H, m),1.74–1.83(1H, m), 1.87–1.98(1H, m), 2.08–2.19(1H, m), 2.22(3H, s),2.72–2.94(10H, m), 3.02(3H, s), 3.41(2H, s), 7.08(2H, d, J=8.4 Hz),7.46(2H, d, J=8.4 Hz), 8.70–9.02(1H, brs), 10.24(1H, s), 11.63(1H, s).

MS: 672.41(M+H)⁺

Step 5

The title compound was prepared from the compound of Step 4 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.29–1.94(4H, m), 2.16(3H, s), 2.77–3.33(15H,m), 4.27–4.46(2H, m), 7.16(2H, d, J=8.3 Hz), 7.27–7.35(2H, m),7.36–7.48(4H, m), 9.8–9.98(1H, m), 10.22–10.51 (1H, brs),12.29–12.36(1H, m).

MS: 472.3(M+H)⁺, 494.2(M+Na)^(+ free)

PRODUCTION EXAMPLE 127 Synthesis of(3R)-1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)-N-methyl-3-piperidinecarboxamidedihydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({(3R)-3-[(methylamino)carbonyl]-1-piperidinyl}methyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound of Step 3 of Production Example 126 in asimilar manner according to Step 1 of Production Example 32.

¹H-NMR (CDCl₃), δ (ppm): 1.50(9H, s), 1.52–1.72(12H, m), 1.84–1.98(1H,m), 2.01–2.14(1H, m), 2.14–2.23(1H, m), 2.24(3H, s), 2.43–2.51(1H, m),2.64–2.76(1H, m), 2.76–2.94(8H, m), 3.32(1H, d, J=14 Hz), 3.41(1H, d,J=14 Hz), 7.06(2H, d, J=8.4 Hz), 7.45(2H, d, J=8.4 Hz), 7.53(1H, brs),8.84(1H, brs), 10.24(1H, s), 11.63(1H, s).

MS: 658.39(M+H)⁺

Step 2

The title compound was prepared from the compound of Step 1 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.31–1.94(4H, m), 2.16(3H, s), 2.54–3.36(12H,m), 4.27–4.48(2H, m), 7.12–7.19(2H, m), 7.25–7.35(2H, m), 7.35(4H, brs),8.05–8.37(1H, m), 9.79–9.92(1H, m), 10.16–10.42(1H, brs),12.29–12.37(1H, m).

MS: 458.2(M+H)⁺, 480.1(M+Na)^(+ free)

PRODUCTION EXAMPLE 128 Synthesis of(3S)-1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)-N,N-dimethyl-3-piperidinecarboxamidedihydrochloride

Step 1

Ethyl(3S)-1-({2-(acetylamino)-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-5-yl}methyl)-3-piperidinecarboxylatewas prepared fromN-{4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide in asimilar manner according to Step 1 of Production Example 67.

MS: 459.21(M+H)⁺

Step 2

Ethyl(3S)-1-[(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)methyl]-3-piperidinecarboxylatewas prepared from the compound of Step 1 in a similar manner accordingto Step 2 of Production Example 68.

¹H-NMR (CDCl₃), δ (ppm): 1.22(3H, t, J=7.2 Hz), 1.3–1.79(21H, m),1.8–2.06(2H, m), 2.08–2.18(1H, m), 2.22(3H, s), 2.43–2.62(1H, m),2.62–2.75(1H, m), 2.84(4H, s), 2.88–3.01(1H, m), 3.42(2H, s), 4.11(2H,q, J=7.1 Hz), 7.08(2H, d, J=8.4 Hz), 7.46(2H, d, J=8.4 Hz),8.71–9.23(1H, brs), 10.24(1H, s), 11.64(1H, s).

MS: 673.3(M+H)⁺, 695.2(M+Na)⁺

Step 3

(3S)-1-[(2-(Acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)methyl]-3-piperidinecarboxylicacid was prepared from the compound of Step 2 in a similar manneraccording to Step 1 of Production Example 42.

MS: 645.36(M+H)⁺

Step 4

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({(3S)-3-[(dimethylamino)carbonyl]-1-piperidinyl}methyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound of Step 3 in a similar manner accordingto Step 1 of Production Example 32.

¹H-NMR (CDCl₃), δ (ppm): 1.4–1.64(20H, m), 1.65–1.73(1H, m),1.73–1.82(1H, m), 1.86–1.97(1H, m), 2.08–2.18(1H, m), 2.22(3H, s),2.7–2.93(10H, m), 3.02(3H, s), 3.41(2H, s), 7.08(2H, d, J=8.4 Hz),7.46(2H, d, J=8.3 Hz), 8.61–8.99(1H, brs), 10.24(1H, s), 11.63(1H, s).

MS: 672.39(M+H)⁺

Step 5

The title compound was prepared from the compound of Step 4 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.29–1.93(4H, m), 2.16(3H, s), 2.77–3.35(15H,m), 4.27–4.45(2H, m), 7.16(2H, d, J=8.4 Hz), 7.28–7.35(2H, m),7.35–7.47(4H, m), 9.8–9.96(1H, m), 10.21–10.46(1H, brs), 12.29–12.36(1H,m).

MS: 472.3(M+H)⁺, 494.2(M+Na)^(+ free)

PRODUCTION EXAMPLE 129 Synthesis of(3S)-1-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)-N-methyl-3-piperidinecarboxamidedihydrochloride

Step 1

Di-tert-butyl{(Z)-[(4-{2-[2-(acetylamino)-5-({(3S)-3-[(methylamino)carbonyl]-1-piperidinyl}methyl)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamatewas prepared from the compound of Step 3 of Production Example 128 in asimilar manner according to Step 1 of Production Example 32.

¹H-NMR (CDCl₃), δ (ppm): 1.46–1.72(21H, m), 1.84–1.97(1H, m),1.99–2.14(1H, m), 2.15–2.22(1H, m), 2.24(3H, s), 2.43–2.51(1H, m),2.65–2.76(1H, m), 2.76–2.91(8H, m), 3.32(1H, d, J=14 Hz), 3.41(1H, d,J=14 Hz), 7.06(2H, d, J=8.4 Hz), 7.45(2H, d, J=8.4 Hz), 7.54(1H, brs),8.84–9.02(1H, brs), 10.24(1H, s), 11.63(1H, s).

MS: 658.40(M+H)⁺

Step 2

The title compound was prepared from the compound of Step 1 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.31–1.94(4H, m), 2.16(3H, s), 2.53–3.36(12H,m), 4.24–4.46(2H, m), 7.12–7.19(2H, m), 7.25–7.35(2H, m), 7.36(4H, brs),8.06–8.37(1H, m), 9.83–9.99(1H, m), 10.28–10.54(1H, brs), 12.33(1H, s).

MS: 458.2(M+H)⁺, 480.2(M+Na)^(+ free)

PRODUCTION EXAMPLE 130 Synthesis ofN-{4-[2-(2-amino-1H-benzimidazol-6-yl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide

Step 1

N-{4-[2-(3,4-Dinitrophenyl)vinyl]-5-[4-(methylthio)benzyl]-1,3-thiazol-2-yl}acetamidewas prepared from2-(acetylamino)-5-[4-(methylthio)benzyl]-1,3-thiazole-4-carbaldehyde ina similar manner according to Step 5 of Production Example 45.

Z:E=3:1

¹H-NMR(CDCl₃), δ (ppm): 2.08(3H×¾, s), 2.12(3H×¼, s), 2.44(3H, s),4.13(2H×¾, s), 4.32(2H×¼, s), 6.71(1H×¾, d, J=12.5 Hz), 6.97(1H×¾, d,J=12.3 Hz), 7.06–8.61(7H+2H×¼, m), 11.85(1H×¾, s), 12.18(1H×¼, s).

MS: 471.1(M+H)⁺, 493.9(M+Na)⁺

Step 2

N-{4-[2-(3,4-Diaminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamidewas prepared from the compound of Step 1 in a similar manner accordingto Step 2 of Production Example 32 and Step 6 of Production Example 45.

¹H-NMR (CDCl₃), δ (ppm): 2.23(3H, s), 2.70–2.85(4H, m), 3.03(3H, s),3.88(2H, s), 6.34(1H, d, J=1.8 Hz), 6.39(1H, dd, J=1.8, 7.8 Hz),6.56(1H, d, J=7.7 Hz), 7.14(2H, d, J=8.3 Hz), 7.79(2H, d, J=8.4 Hz),8.30–9.45(1H, brs).

MS: 445.0(M+H)⁺, 467.0(M+Na)⁺

Step 3

To a suspension ofN-{4-[2-(3,4-diaminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide(70.8 mg) in MeOH (0.7 ml) was added cyanogen bromide (25.3 mg), thenthe mixture was stirred for 14 h at 20° C. To the reaction mixture wasadded 1N—NaOH (0.239 ml) and the mixture was concentrated in vacuo. Tothe residue was added CHCl₃: MeOH=10:1 (10 ml), and an insolublematerial was removed by filtration. The filtrate was purified by flashcolumn chromatography over NH silica gel with CHCl₃/MeOH (100:1→10:1) asan eluent to give colorless oil. The oil was solidified with CH₂Cl₂:Et₂O=2:1 to giveN-{4-[2-(2-amino-1H-benzimidazol-6-yl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamideas a white solid.

¹H-NMR (CDCl₃), δ (ppm): 2.09(3H, s), 2.85(4H, s), 3.16(3H, s), 3.97(2H,s), 6.01(2H, s), 6.55–6.77(1H, m), 6.78–6.90(1H, m), 6.96(1H, d, J=7.8Hz), 7.10–7.30(2H, brs), 7.72(2H, d, J=8.1 Hz), 10.55(1H, d, J=10.5 Hz),11.50–12.20(1H, brs).

MS: 470.2(M+H)⁺, 492.1(M+Na)⁺

PRODUCTION EXAMPLE 131 Synthesis ofN-{4-[2-(2-amino-1H-benzimidazol-6-yl)ethyl]-1,3-thiazol-2-yl}acetamide

Step 1

N-{4-[2-(3,4-Dinitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide wasprepared from 2-(acetylamino)-1,3-thiazole-4-carbaldehyde in a similarmanner according to Step 5 of Production Example 1.

Z:E=8:1

¹H-NMR (DMSO-d₆), δ (ppm): 2.13(3H× 8/9, s), 2.17(3H× 1/9, s), 6.64(1H×8/9, d, J=12.6 Hz), 6.80(1H× 8/9, d, J=12.6 Hz), 7.29(1H× 1/9, d, J=15.7Hz), 7.33(1H× 8/9, s), 7.39(1H× 1/9, s), 7.63(1H× 1/9, d, J=15.7 Hz),8.00–8.50(3H, m), 11.97(1H× 8/9, s), 12.30(1H× 1/9, s)

MS: 335.0(M+H)⁺, 357.1(M+Na)⁺

Step 2

N-{4-[2-(3,4-Diaminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide wasprepared from the compound of Step 1 in a similar manner according toStep 6 of Production Example 1.

¹H-NMR (CDCl₃), δ (ppm): 2.22(3H, s), 2.58–3.17(8H, m), 6.46–6.56(3H,m), 6.62(1H, d, J=8.3 Hz), 8.84–10.42(1H, brs).

MS: 277.1(M+H)⁺, 299.2(M+Na)⁺

Step 3

The title compound was prepared from the compound of Step 2 in a similarmanner according to Step 3 of Production Example 130.

¹H-NMR (CDCl₃), δ (ppm): 2.11(3H, s), 2.79–2.97(4H, m), 6(2H, s),6.59–6.8(2H, m), 6.91(1H, s), 6.97(1H, d, J=7.9 Hz), 10.34–10.73(1H,brs), 11.94–12.22(1H, brs).

MS: 302.2(M+H)⁺, 324.1(M+Na)⁺

PRODUCTION EXAMPLE 132 Synthesis ofN-({2-(acetylamino)-4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-5-yl}methyl)-N-methylacetamidehydrochloride

Step 1

N-{5-[(Methylamino)methyl]-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamidewas prepared fromN-{4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide in asimilar manner according to Step 1 of Production Example 67.

¹H-NMR (CDCl₃), δ (ppm): 2.05(3H, s), 2.46(3H, s), 3.75(2H, s), 6.67(2H,s), 7.41(2H, d, J=8.9 Hz), 8.01(2H, d, J=8.8 Hz), 9.7–11.69(1H, brs).

MS: 333.1(M+H) t, 355.1(M+Na)⁺

Step 2

To a suspension ofN-{5-[(methylamino)methyl]-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide(46.8 mg) in dichloromethane (0.5 ml) were addedN,N-diisopropylehtylamine (27 μl) and acethyl chloride (10 μl), and themixture was stirred for 2 h at 20° C. To the reaction mixture were addeddichloromethane (5 ml), N,N-diisopropylehtylamine (27 μl) and acethylchloride (10 μl), and the mixture was stirred for 5 min. at 20° C., thenwashed with saturated sodium hydrogen carbonate aqueous solution (5 ml)and brine (5 ml), dried over MgSO₄, filtered and evaporated to give ayellow solid (67.8 mg). The crude compound was purified by preparativesilica gel thin-layer chromatography with chloroform/methanol (20:1) asan eluent to giveN-({2-(acetylamino)-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-5-yl}methyl)-N-methylacetamideas a yellow solid.

¹H-NMR (CDCl₃), δ (ppm): 2.12(3H×⅔, s), 2.13(3H×⅓, s), 2.14(3H×⅔, s),2.24(3H×⅓, s), 3.02(3H×⅔, s), 3.05(3H×⅓, s), 4.62(2H×⅔, s), 4.79(2H×⅓,s), 6.61(1H×⅓, d, J=12.6 Hz), 6.70(1H×⅔, d, J=12.6 Hz), 6.77(1H×⅓, d,J=12.6 Hz), 6.82(1H×⅔, d, J=12.6 Hz), 7.43(2H×⅔, d, J=8.8 Hz),7.65(2H×⅓, d, J=8.8 Hz), 8.06(2H×⅔, d, J=8.8 Hz), 8.22(2H×⅓, d, J=8.8Hz), 9.09–9.26(1H×⅓, brs), 9.26–9.51(1H×⅔, brs).

MS: 375.2(M+H)⁺, 397.1(M+Na)⁺

Step 3

N-({2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-5-yl}methyl)-N-methylacetamide was prepared from thecompound of Step 2 in a similar manner according to Step 6 of ProductionExample 45.

MS: 347.25(M+H)⁺

Step 4

Di-tert-butyl[(Z)-({4-[2-(2-(acetylamino)-5-{[acetyl(methyl)amino]methyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared from the compound of Step 3 in a similar manner accordingto Step 3 of Production Example 31.

¹H-NMR (CDCl₃), δ (ppm): 1.49(9H, s), 1.53(9H, s), 2.06(3H×¾, s),2.12(3H×¼, s), 2.23(3H, s), 2.77(3H×¼, s), 2.81(3H×¾, s), 2.90(4H, s),4.20(2H×¼, s), 4.46(2H×¾, s), 7.01(2H×¼, d, J=8.6 Hz), 7.07(2H×¾, d,J=8.5 Hz), 7.43(2H×¾, d, J=8.5 Hz), 7.46(2H×¼, d, J=8.0 Hz),8.81–9.09(1H, brs), 10.22(1H×¾, s), 10.25(1H×¼, s), 11.62(1H, s).

MS: 589.2(M+H)⁺, 611.2(M+Na)⁺

Step 5

The title compound was prepared from the compound of Step 4 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (DMSO-d₆), δ (ppm): 1.98(3H×¾, s), 2.02(3H×¼, s), 2.11(3H×¾, s),2.12(3H×¼, s), 2.60(3H×¼, s), 2.82(3H×¾, s), 2.89(4H, s), 4.39(2H×¾, s),4.45(2H×¼, s), 7.13(2H×¼, d, J=8.1 Hz), 7.14(2H×¾, d, J=8.4 Hz),7.22(2H×¼, d, J=8.4 Hz), 7.25(2H×¾, d, J=8.4 Hz), 7.31(4H, s), 9.61(1H,s), 12.03(1H×¾, s), 12.13(1H×¼, s).

MS: 389.19(M+H)^(+ free)

PRODUCTION EXAMPLE 133 Synthesis ofN-[4-(2-{4-[(2-aminoethyl)amino]phenyl}ethyl)-1,3-thiazol-2-yl]acetamidedihydrochloride

Step 1

To a suspension ofN-{4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (100 mg) intoluene were added tert-butyl (2-bromoethyl)carbamate (87.5 mg) andN,N-diisopropylethylamine (52 μl), and the mixture was stirred at 80° C.for 24 h. The reaction mixture was allowed to cool to room temperature,water (10 ml) was added, and the organic layer was separated, washedwith saturated aqueous NaCl, dried over MgSO₄, filtered, andconcentrated in vacuo to give tert-butyl{2-[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]ethyl}carbamateas a pale brown amorphous.

¹H-NMR (CDCl₃), δ (ppm): 1.45(9H, s), 2.23(3H, s), 2.86(4H, s),3.15–3.28(2H, m), 3.15–3.47(2H, m), 4.64–5.02(1H, brs), 6.49(1H, s),6.52(2H, d, J=8.0 Hz), 6.95(2H, d, J=8.0 Hz), 9.22–10.10(1H, brs).

MS: 405.2(M+H)⁺, 427.3(M+Na)⁺

Step 2

The title compound was prepared from the compound of Step 2 in a similarmanner according to Step 2 of Production Example 10.

¹H-NMR (DMSO-d₆), δ (ppm): 2.11(3H, s), 2.81(4H, s), 2.92–3.05(2H, m),3.29(2H, t, J=6.2 Hz), 6.67(2H, d, J=7.7 Hz), 7.01(2H, d, J=8.1 Hz),7.87–8.24(3H, brs), 12.08(1H, s).

MS: 305.2(M+H)⁺, 327.2(M+Na)⁺

PRODUCTION EXAMPLE 134 Synthesis ofN-{4-[3-(2-{[amino(imino)methyl]amino}ethyl)phenyl]-1,3-thiazol-2-yl}acetamidehydrochloride

Step 1

To a suspension of lithium aluminium hydride in dry tetrahydrofuran (50ml) was added (3-bromophenyl)acetic acid (10 g) in tetrahydrofuran (100ml) under ice cooling. The mixture was refluxed for 2 hurs. Aftercooling, to the reaction mixture were added water and aqueous Rochellesalt.

The mixture was stirred for another 30 min. Aqueous layer was extractedwith ethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate, and concentrated in vacuo to give 2-(3-bromophenyl)ethanol.This compound was used for the next reaction without furtherpurification.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 1.66(1H, brs), 2.84(2H, dd, J=6.5, 14Hz), 3.85(2H, dt, J=6.5, 2.6 Hz), 7.13–7.39(4H, m).

Step 2

To a solution of 2-(3-bromophenyl)ethanol (7 g) in N,N-dimethylformamide(100 ml) were added tert-butyldimethylsilyl chloride (5.77 g) andimidazole (2.84 g) at 25° C. The mixture was stirred at 25° C. for 12 h.The reaction mixture was poured into water (500 ml) and extracted withethyl acetate (100 ml×2). The combined organic layer was dried overmagnesium sulfate and concentrated in vacuo. The residue was purified bysilica gel column chromatography with mixed solvent of n-hexane andethyl acetate to give[2-(3-bromophenyl)ethoxy](tert-butyl)dimethylsilane as colorless oil.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 0.01(6H, s), 0.88(9H, s), 2.81(2H, dt,J=6.5, 9.5 Hz), 3.81(2H, dt, J=3.0, 6.5 Hz), 7.14–7.39 (5H, brs).

Step 3

To a solution of 1.6 g of[2-(3-bromophenyl)ethoxy](tert-butyl)dimethylsilane in tetrahydrofuran(20 ml) was added n-BuLi in hexane (1.57M, 3.88 ml) at −70° C., then thereaction mixture was stirred at same temperature for 30 min. To thesolution was added dimethylacetamide (1.42 ml) drop wise at the sametemperature. The mixture was stirred for another 1 hour. To the reactionmixture were added water and 8 ml of 1N HCl under ice-cooling. Themixture was stirred for 1 hour, then extracted with ethyl acetate. Theorganic layer was washed with brine, dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography with n-hexane and ethyl acetate (20/1–10/1) as an eluentto give 1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]ethanone(350 mg) as colorless oil.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 0.03(6H, s), 0.85(9H, s), 2.61(3H, s),2.87(2H, t, J=6.7 Hz), 3.82(2H, t, J=6.7 Hz), 7.20–7.24(1H, m),7.35–7.44(2H, m), 7.77–7.82(2H, m).

MS: 279(M+H)⁺

Step 4

To a solution of1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]ethanone (755 mg)in tetrahydrofuran (4 ml) was added bromine (168 ml) drop wise at 0° C.The mixture was stirred at 25° C. for 1 h. To the reaction mixture wasadded aq. saturated NaHCO₃, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate and concentrated under reduced pressure to give crude of2-bromo-1-[3-(2-hydroxyethyl)phenyl]ethanone as colorless oil. Thiscompound was used for the next reaction without further purification.

Step 5

To a solution of 2-bromo-1-[3-(2-hydroxyethyl)phenyl]ethanone (crude,658 mg) in tetrahydrofuran (15 ml) was added 1-acetyl-2-thiourea (320mg) at 25° C. The mixture was stirred at 60° C. for 2 h. The residualcolorless crystals were collected by filtration. The crystals werewashed with isopropyl ether, dried under reduced pressure to giveN-{4-[3-(2-hydroxyethyl)phenyl]-1,3-thiazol-2-yl}acetamide (514 mg) as acolorless crystal.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.16(3H, s), 2.76(2H, t, J=6.9 Hz),3.63(2H, t, J=6.9 Hz), 4.89(1H, brs), 7.16(1H, d, J=7.7 Hz), 7.32(1H,dd, J=7.7, 7.6 Hz), 7.56(1H, s), 7.70(2H, d, J=7.6 Hz), 7.76(1H, s),12.24(1H, s).

MS: 263(M+H)⁺

Step 6

To a suspension ofN-{4-[3-(2-hydroxyethyl)phenyl]-1,3-thiazol-2-yl}acetamide (300 mg) inCH₂Cl₂ (10 ml) were added methansulfonyl chloride (106 μl) andtriethylamine (207 μl) at 5° C. The mixture was stirred at 25° C. for 2h. The reaction mixture was poured into water and extracted withdichloromethane. The organic layer was washed with brine, dried overmagnesium sulfate and concentrated under reduced pressure. Resultingresidue was purified by silica gel column chromatography with n-hexaneand ethyl acetate (1:1) as an eluent to give2-{3-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl methanesulfonate(388 mg) as a colorless solid.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.16(3H, s), 3.04(2H, t, J=6.9 Hz),3.12(3H, s), 4.45(2H, t, J=6.9 Hz), 7.23–7.42(2H, m), 7.60(1H, s),7.75–7.81(2H, m), 12.26(1H, s).

MS: 341(M+H)⁺

Step 7

To a solution of 2-{3-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethylmethanesulfonate (388 mg) in N,N-dimethylformamide (5-ml) were addeddi-tert-butyliminodicarboxylate (322 mg) and K₂CO₃ (236 mg) at 25° C.The mixture was stirred at 80° C. for 2 hours. The reaction mixture waspoured into water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over magnesium sulfate and concentratedunder reduced pressure. Resulting colorless oil containingN-{4-(3-[2-{di-(tert-butoxycarbonyl)amino}ethyl]phenyl)-1,3-thiazol-2-yl}acetamidewas used for the next reaction without further purification.

Step 8

N-{4-[3-(2-Aminoethyl)phenyl]-1,3-thiazol-2-yl}acetamide was preparedfrom the compound of Step 7 in a similar manner according to Step 2 ofProduction Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.16(1H, s), 2.74(2H, dd, J=6.8, 6.2Hz), 2.88(2H, dd, J=7, 7.8 Hz), 7.17(1H, d, J=7.7 Hz), 7.35(1H, dd,J=7.7, 8 Hz), 7.58(1H, s), 7.73(1H, d, J=8 Hz), 7.74(1H, s).

MS: 262(M+H)⁺

Step 9

Di-tert-butyl{(Z)-[(2-{3-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl)amino]methylidene}biscarbamatewas prepared from the compound of Step 8 in a similar manner accordingto Step 5 of Production Example 18.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 1.45(9H, s), 1.50(3H, s), 2.27(3H, s),2.92(2H, t, J=7.5 Hz), 3.71(2H, dt, J=7.5, 7.2 Hz), 7.11–7.41(4H, d),7.65–7.78(1H, m).

MS: 504(M+H)⁺

Step 10

The title compound was prepared from the compound of Step 9 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 2.16(3H, s), 2.83(2H, t, J=6.9 Hz),3.41(2H, m), 7.23(1H, d, J=7.7 Hz), 7.38(1H, dd, J=7.7, 7.8 Hz),7.52(1H, t, J=5.5 Hz), 7.59(1H, s), 7.75(1H, d, J=8.1 Hz), 7.79(1H, s),12.23(1H, s).

MS: 304(M+H)^(+ free)

PRODUCTION EXAMPLE 135 Synthesis ofN-(4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-{2-[4-(methylsulfonyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamidehydrochloride

Step 1

tert-ButylN-{4-[2-(2-(acetylamino)-5-{(E)-2-[4-(methylsulfonyl)phenyl]vinyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamatewas prepared from2-(acetylamino)-4-{2-[4-(tert-butoxycarbonylamino)phenyl]ethyl}-1,3-thiazole-5-carbaldehydein a similar manner according to Step 5 of Production Example 45.

MS: 542(M+H)^(+ free)

Step 2

tert-ButylN-{4-[2-(2-(acetylamino)-5-{2-[4-(methylsulfonyl)phenyl]ethyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamatewas prepared from the compound of Step 1 in a similar manner accordingto Step 6 of Production Example 45.

MS: 544(M+H)⁺

Step 3

N-(4-[2-(4-Aminophenyl)ethyl]-5-{2-[4-(methylsulfonyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamidewas prepared from the compound of Step 2 in a similar manner accordingto Step 2 of Production Example 31.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 2.23(3H, s), 2.61(4H, s), 2.78(4H, s),2.98(3H, s), 3.55(2H, brs), 6.57(2H, d, J=8.5 Hz), 6.81(2H, d, J=8.5Hz), 7.25(2H, d, J=8.5 Hz), 7.82(2H, d, J=8.5 Hz), 8.80(1H, s).

MS: 444(M+H)⁺

Step 4

Di-tert-butyl[(E)-({4-[2-(2-(acetylamino)-5-{2-[4-(methylsulfonyl)phenyl]ethyl}-1,3-thiazol-4-yl)ethyl]phenyl}amino)methylidene]biscarbamatewas prepared from the compound of Step 3 in a similar manner accordingto Step 5 of Production Example 18.

¹H-NMR (200 MHz, CDCl₃), δ (ppm): 1.49(9H, s), 1.53(9H, s), 2.22(3H, s),2.59–2.73(4H, m), 2.84(4H, s), 2.98(3H, s), 6.99(2H, d, J=8.4 Hz),7.28(2H, d, J=8.4 Hz), 7.44(2H, d, J=8.4 Hz), 7.83(2H, d, J=8.4 Hz),8.99(1H, bra), 10.23(1H, s), 11.62(1H, s).

MS: 686(M+H)⁺

Step 5

The title compound was prepared from the compound of Step 4 in a similarmanner according to Step 4 of Production Example 31.

¹H-NMR (200 MHz, DMSO-d₆), δ (ppm): 2.16(3H, s), 2.67(4H, brs),2.82–2.94(4H, m), 3.14(3H, s), 7.12(2H, d, J=8.4 Hz), 7.20(2H, d, J=8.4Hz), 7.43(2H, d, J=8.4 Hz), 7.82(2H, d, J=8.4 Hz), 9.87(1H, s),11.97(1H, s).

MS: 486(M+H)⁺

The compounds according to the present invention useful as VAP-1inhibitors are listed in the following tables.

No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

EXAMPLE 1

Inhibitory Effect of Compound A on VAP-1 enzyme (SSAO) Activity in Humanand Rat Plasma.

VAP-1 enzyme (SSAO) activity in both human and rat plasma was determinedby a radiochemical-enzyme assay using ¹⁴C-benzylamine as artificialsubstrate. The enzyme suspension prepared from blood plasma waspre-incubated with Compound A in 96-well microplate at room temperaturefor 30 min. The enzyme suspension was then incubated with¹⁴C-benzylamine (2×10⁻⁵ mol/l final concentration) in a final volume of50 μl at 37° C. for 1 hour. The enzyme reaction was terminated by adding2 mol/l (50 μl) citric acid. The oxidized products were directlyextracted into a 200 μl toluene scintillator, and its radioactivity wasmeasured by a scintillation spectrometer. Monoamine oxidase (MAO) anddiamine oxidase (DAO, histaminase) activities were also determined bysimilar method using ¹⁴C-phenylethylamine and ¹⁴C-putrescine assubstrate, respectively. Cloned DAO from cDNA libraries was used inhuman DAO assay. Inhibition activity was expressed as IC₅₀ (μmol/l)value.

Compound A completely inhibited the enzyme activity of human and ratplasma SSAO, but not the enzyme activities of other amine oxidases, suchas human platelet MAO and cloned DAO, shown in Table 1.

TABLE 1 Inhibitory effect (IC₅₀ values, μM) of Compound A on variousamine oxidase activities Human Rat Human Cloned plasma plasma platelethuman SSAO SSAO MAO DAO 0.15 0.012 >100 >100

EXAMPLE 2

Effect of Compound A on Ocular Permeability in Diabetic Rats.

Diabetes in rat was induced with an intraperitoneal (i.p.) injection of65 mg/ml/kg of streptozotocin (STZ) in 2 mmol/l citrate buffer (pH 4.5)after a 20-h fast. At the same time control rat were injected with anequal volume of 2 mmol/l citrate buffer. Plasma glucose level waschecked by a colorimetric method. At day 3 of STZ treatment, the rat wasdiagnosed with diabetes showing a plasma glucose level of 350 mg/dl.

The treatment of Compound A was given daily from 2 weeks after STZtreatment for 2 weeks. At 24 hrs after final treatment of Compound A,the vascular permeability in oculus was investigated based on theleakage of dye into the vitreous 30 min after intravenous injection offluorescein solution (40 mg/ml/kg). Permeability was expressed asvitreous/plasma ratio of fluorescein concentration measured by afluorophotometer. At the same time, the plasma SSAO activity was checkedby the radiochemical-enzyme assay using ¹⁴C-benzylamine (2×10⁻⁵ mol/lfinal concentration) as substrate.

The significant increase of ocular permeability in diabetic rats wasexamined at 4 weeks after treatment of STZ and compared with that ofnormoglycemic normal rats. The treatment of Compound A (10 mg/kg, s.c.u.i.d.) given daily from 2 weeks after STZ treatment improved the ocularpermeability, in comparison with the STZ control group (Table 2). PlasmaSSAO enzyme activity also increased in diabetic rats at 4 weeks afterSTZ treatment, but the treatment with Compound A exhibiteddose-dependent inhibition of the increased plasma SSAO activity (Table3).

TABLE 2 Vitreous/Plasma Ratio of Fluorescein Concentration (×10⁻³)Compound A Normal STZ control treatment 3.30 ± 0.38** 8.93 ± 1.14 5.39 ±0.73** Values are mean ± S.E.M.s for 10 rats. **p < 0.01 vscorresponding value for STZ control by Dunnett's test.

TABLE 3 Plasma SSAO activity (pmol/min/ml) Compound A Normal STZ controltreatment 4.40 ± 0.34** 10.0 ± 0.73 2.51 ± 0.26** Values are mean ±S.E.M.s for 10 rats. **p < 0.01 vs corresponding value for STZ controlby Dunnett's test. U.S. 60/442,509; 60/458,369; and 60/517,377 are eachincorporated herein by reference in their entirety.

INDUSTRIAL APPLICABILITY

The present invention provides a compound of the formula (I):R¹—NH—X—Y-Z (I)

wherein each symbol is as defined above, or a parmaceutically acceptablesalt thereof useful as a VAP-1 inhibitor, a pharmaceutical composition,a method for preventing or treating a VAP-1 associated disease,especially macular edema such as diabetic macular edema and non-diabeticmacular edema, which method comprises administering to a patient in needthereof a VAP-1 inhibitor in an amount sufficient to treat the patientfor the VAP-1 associated disease, and the like.

1. A compound of the formula (I):

wherein the 1,3-thiazole ring is optionally substituted at the5-position; Y is lower alkylene, lower alkenylene or —CONH—; and Z is agroup of the formula:

wherein R² is a group of the formula: -A-B-D-E, wherein A is a bond,lower alkylene, —NH— or —SO₂—; B is a bond, lower alkylene, —CO— or —O—;D is a bond, lower alkylene, —NH— or —CH₂NH—; provided that B and D arenot both simultaneously bonds, and E is amino, which may be optionallyprotected, —N═CH₂,

wherein Q is —S— or —NH—; and R³ is hydrogen, lower alkyl, loweralkylthio, or —NH—R⁴, wherein R⁴ is hydrogen, —NH₂ or lower alkyl; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein Z is a group of the formula:

wherein R² is a group of the formula:

(wherein G is a bond, —NHCOCH₂— or lower alkylene and R⁴ is hydrogen,—NH₂ or lower alkyl); —NH₂; —CH₂NH₂; —CH₂ONH₂; —CH₂ON═CH₂;

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim2, wherein R² is a group of the formula:

(wherein G is a bond, —NHCOCH₂— or lower alkylene and R⁴ is hydrogen orlower alkyl); —CH₂NH₂; —CH₂ONH₂; —CH₂ON═CH₂;

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, wherein the compound is:N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide,N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide,N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,orN-(4-{2-[4-(2-{[amino(imino)methyl]amino}ethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide;or a pharmaceutically acceptable salt thereof.
 5. A pharmaceuticalcomposition, which comprises: the compound of claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticalyacceptable carrier or excipient.
 6. A method for producing a compound offormula (I):

wherein the 1,3-thiazole ring is optionally substituted at the5-position; Y is lower alkylene, lower alkenylene or —CONH—; and Z is agroup of the formula:

wherein R² is a group of the formula: -A-B-D-E wherein A is a bond,lower alkylene, —NH— or —SO₂—; B is a bond, lower alkylene, —CO— or —O—;D is a bond, lower alkylene, —NH— or —CH₂NH—; provided that B and D arenot simultaneously bonds, and E is amino, which is optionally protected,—N═CH₂,

 wherein Q is —S— or —NH—; and R³ is hydrogen, lower alkyl, loweralkylthio or —NH—R⁴, wherein R⁴ is hydrogen, —NH₂ or lower alkyl; or apharmaceutically acceptable salt thereof; which method comprises atleast one step selected from the group consisting of (ii), (iii), (iv)and (v): (ii) reacting Compound (3):

 wherein Z is as defined above and the 1,3-thiazole ring is optionallysubstituted at the 5-position, or a salt thereof with Compound (4):

 wherein L₂ is a leaving group; (iii) reacting Compound (6):

 wherein the 1,3-thiazole ring is optionally substituted at the5-position or a salt thereof with Compound (7): L₃-CH₂-Z, wherein L₃ isa leaving group and Z is as defined above, or a salt thereof; (iv)reduction of Compound (10):

wherein Z is as defined above and the 1,3-thiazole ring is optionallysubstituted at the 5-position, or a salt thereof; to Compound (11):

 wherein Z is as defined above and the 1,3-thiazole ring is optionallysubstituted at the 5-position; or a salt thereof; and (v) reactingCompound (12):

 wherein the 1,3-thiazole ring is optionally substituted at the5-position or a reactive derivative thereof, or a salt thereof withCompound (13): L₄-NH-Z, wherein L⁴ is a hydrogen atom or a protectinggroup and Z is as defined above; or a salt thereof.
 7. A method fortreating macular edema comprising: administering to a subject in needthereof the compound of claim 1 in an amount sufficient to treat saidsubject for macular edema.
 8. The method of claim 7, wherein thecompound is:N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide,N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide,N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,orN-(4-{2-[4-(2-{[amino(imino)methyl]amino}ethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide,or a pharmaceutically acceptable salt thereof.
 9. The method of claim 7,wherein said macular edema is diabetic macular edema.
 10. The method ofclaim 7, wherein said macular edema is non-diabetic macular edema.